Glucopyranoside compound

ABSTRACT

A compound of the formula: 
                         
wherein Ring A and Ring B are: (1) Ring A is an optionally substituted unsaturated monocyclic heterocyclic ring, and Ring B is an optionally substituted unsaturated monocyclic heterocyclic ring, an optionally substituted unsaturated fused heterobicyclic ring, or an optionally substituted benzene ring, (2) Ring A is an optionally substituted benzene ring, and Ring B is an optionally substituted unsaturated monocyclic heterocyclic ring or an optionally substituted unsaturated fused heterobicyclic ring, or (3) Ring A is an optionally substituted unsaturated fused heterobicyclic ring, and Ring B are independently an optionally substituted unsaturated monocyclic heterocyclic ring, an optionally substituted unsaturated fused heterobicyclic ring, or an optionally substituted benzene ring; X is a carbon atom or a nitrogen atom;
     Y is —(CH 2 ) n — (n is 1 or 2);
 
a pharmaceutically acceptable salt thereof, or a prodrug thereof.

This application is a Continuation-In-Part of co-pending PCTInternational Applications No. PCT/JP2004/011312 filed on Jul. 30, 2004,which designated the United States and on which priority is claimedunder 35 U.S.C. §120, which claims priority of Provisional ApplicationNo. 60/491,534 filed Aug. 1, 2003, the entire contents of which arehereby incorporated by reference.

TECHNICAL FIELD

The present invention relates to a novel compound having an inhibitoryactivity against sodium-dependent glucose transporter (SGLT) beingpresent in the intestine or kidney.

BACKGROUND ART

Diet therapy and exercise therapy are essential in the treatment ofdiabetes mellitus. When these therapies do not sufficiently control theconditions of patients, insulin or an oral antidiabetic agent isadditionally used for the treatment of diabetes. At the present, therehave been used as an antidiabetic agent biguanide compounds,sulfonylurea compounds, insulin resistance improving agents andα-glucosidase inhibitors. However, these antidiabetic agents havevarious side effects. For example, biguanide compounds cause lacticacidosis, sulfonylurea compounds cause significant hypoglycemia, insulinresistance improving agents cause edema and heart failure, andα-glucosidase inhibitors cause abdominal bloating and diarrhea. Undersuch circumstances, it has been desired to develop novel drugs fortreatment of diabetes mellitus having no such side effects.

Recently, it has been reported that hyperglycemia participates in theonset and progressive impairment of diabetes mellitus, i.e., glucosetoxicity theory. Namely, chronic hyperglycemia leads to decrease ofinsulin secretion and further to decrease of insulin sensitivity, and asa result, the blood glucose concentration is increased so that diabetesmellitus is self-exacerbated [cf., Diabetologia, vol. 28, p. 119 (1985);Diabetes Care, vol. 13, p. 610 (1990), etc.]. Therefore, by treatinghyperglycemia, the aforementioned self-exacerbating cycle is interruptedso that the prophylaxis or treatment of diabetes mellitus is madepossible.

As one of the methods for treating hyperglycemia, it is considered toexcrete an excess amount of glucose directly into urine so that theblood glucose concentration is normalized. For example, by inhibitingsodium-dependent glucose transporter being present at the proximalconvoluted tubule of kidney, the re-absorption of glucose at the kidneyis inhibited, by which the excretion of glucose into urine is promotedso that the blood glucose level is decreased. In fact, it is confirmedthat by continuous subcutaneous administration of phlorizin having SGLTinhibitory activity to diabetic animal models, hyperglycemia isnormalized and the blood glucose level thereof can be kept normal for along time so that the insulin secretion and insulin resistance areimproved [cf., Journal of Clinical Investigation, vol. 79, p. 1510(1987); ibid., vol. 80, p. 1037 (1987); ibid., vol. 87, p. 561 (1991),etc.].

In addition, by treating diabetic animal models with SGLT inhibitoryagents for a long time, insulin secretion response and insulinsensitivity of the animals are improved without incurring any adverseaffects on the kidney or imbalance in blood levels of electrolytes, andas a result, the onset and progress of diabetic nephropathy and diabeticneuropathy are prevented [cf., Journal of Medicinal Chemistry, vol. 42,p. 5311 (1999); British Journal of Pharmacology, vol. 132, p. 578(2001), Ueta, Ishihara, Matsumoto, Oku, Nawano, Fujita, Saito, Arakawa,Life Sci., in press (2005), etc.].

From the above, SGLT inhibitors may be expected to improve insulinsecretion and insulin resistance by decreasing the blood glucose levelin diabetic patients and further prevent the onset and progress ofdiabetes mellitus and diabetic complications.

WO 01/27128 discloses an aryl C-glycoside compound having the followingstructure.

This compound is disclosed to be useful in the prophylaxis or treatmentof diabetes mellitus, etc., as an SGLT inhibitor.

DISCLOSURE OF INVENTION

The present invention relates to a compound of the following formula I,or a pharmaceutically acceptable salt thereof, or a prodrug thereof:

wherein Ring A and Ring B are one of the followings: (1) Ring A is anoptionally substituted unsaturated monocyclic heterocyclic ring, andRing B is an optionally substituted unsaturated monocyclic heterocyclicring, an optionally substituted unsaturated fused heterobicyclic ring,or an optionally substituted benzene ring, (2) Ring A is an optionallysubstituted benzene ring, and Ring B is an optionally substitutedunsaturated monocyclic heterocyclic ring, or an optionally substitutedunsaturated fused heterobicyclic ring wherein Y is linked to theheterocyclic ring of the fused heterobicyclic ring, or (3) Ring A is anoptionally substituted unsaturated fused heterobicyclic ring, whereinthe sugar moiety X— (sugar) and the moiety —Y— (Ring B) are both on thesame heterocyclic ring of the fused heterobicyclic ring, and Ring B isan optionally substituted unsaturated monocyclic heterocyclic ring, anoptionally substituted unsaturated fused heterobicyclic ring, or anoptionally substituted benzene ring;

X is a carbon atom or a nitrogen atom; and

Y is —(CH₂)_(n)— (wherein n is 1 or 2).

The compound of the formula I exhibits an inhibitory activity againstsodium-dependent glucose transporter being present in the intestine andthe kidney of mammalian species, and is useful in the treatment ofdiabetes mellitus or diabetic complications such as diabeticretinopathy, diabetic neuropathy, diabetic nephropathy, obesity, anddelayed wound healing.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present compound (I) is illustrated in more detail.

The definitions for each term used in the description of the presentinvention are listed below.

The term “halogen atom” or “halo” means chlorine, bromine, fluorine andiodine, and chlorine and fluorine are preferable.

The term “alkyl group” means a straight or branched saturated monovalenthydrocarbon chain having 1 to 12 carbon atoms. The straight chain orbranched chain alkyl group having 1 to 6 carbon atoms is preferable, andthe straight chain or branched chain alkyl group having 1 to 4 carbonatoms is more preferable. Examples thereof are methyl group, ethylgroup, propyl group, isopropyl group, butyl group, t-butyl group,isobutyl group, pentyl group, hexyl group, isohexyl group, heptyl group,4,4-dimethylpentyl group, octyl group, 2,2,4-trimethylpentyl group,nonyl group, decyl group, and various branched chain isomers thereof.Further, the alkyl group may optionally and independently be substitutedby 1 to 4 substituents as listed below, if necessary.

The term “alkylene group” or “alkylene” means a straight or brancheddivalent saturated hydrocarbon chain having 1 to 12 carbon atoms. Thestraight chain or branched chain alkylene group having 1 to 6 carbonatoms is preferable, and the straight chain or branched chain alkylenegroup having 1 to 4 carbon atoms is more preferable. Examples thereofare methylene group, ethylene group, propylene group, trimethylenegroup, etc. If necessary, the alkylene group may optionally besubstituted in the same manner as the above-mentioned “alkyl group”.

Where alkylene groups as defined above attach at two different carbonatoms of the benzene ring, they form an annelated five, six or sevenmembered carbocycle together with the carbon atoms to which they areattached, and may optionally be substituted by one or more substituentsdefined below.

The term “alkenyl group” means a straight or branched monovalenthydrocarbon chain having 2 to 12 carbon atoms and having at least onedouble bond. Preferable alkenyl group is a straight chain or branchedchain alkenyl group having 2 to 6 carbon atoms, and the straight chainor branched chain alkenyl group having 2 to 4 carbon atoms is morepreferable. Examples thereof are vinyl group, 2-propenyl group,3-butenyl group, 2-butenyl group, 4-pentenyl group, 3-pentenyl group,2-hexenyl group, 3-hexenyl group, 2-heptenyl group, 3-heptenyl group,4-heptenyl group, 3-octenyl group, 3-nonenyl group, 4-decenyl group,3-undecenyl group, 4-dodecenyl group, 4,8,12-tetradecatrienyl group,etc. The alkenyl group may optionally and independently be substitutedby 1 to 4 substituents as mentioned below, if necessary.

The term “alkenylene group” means a straight or branched divalenthydrocarbon chain having 2 to 12 carbon atoms and having at least onedouble bond. The straight chain or branched chain alkenylene grouphaving 2 to 6 carbon atoms is preferable, and the straight chain orbranched chain alkenylene group having 2 to 4 carbon atoms is morepreferable. Examples thereof are vinylene group, propenylene group,butadienylene group, etc. If necessary, the alkylene group mayoptionally be substituted by 1 to 4 substituents as mentioned below, ifnecessary.

Where alkenylene groups as defined above attach at two different carbonatoms of the benzene ring, they form an annelated five, six or sevenmembered carbocycle (e.g., a fused benzene ring) together with thecarbon atoms to which they are attached, and may optionally besubstituted by one or more substituents defined below.

The term “alkynyl group” means a straight or branched monovalenthydrocarbon chain having at least one triple bond. The preferablealkynyl group is a straight chain or branched chain alkynyl group having2 to 6 carbon atoms, and the straight chain or branched chain alkynylgroup having 2 to 4 carbon atoms is more preferable. Examples thereofare 2-propynyl group, 3-butynyl group, 2-butynyl group, 4-pentynylgroup, 3-pentynyl group, 2-hexynyl group, 3-hexynyl group, 2-heptynylgroup, 3-heptynyl group, 4-heptynyl group, 3-octynyl group, 3-nonynylgroup, 4-decynyl group, 3-undecynyl group, 4-dodecynyl group, etc. Thealkynyl group may optionally and independently be substituted by 1 to 4substituents as mentioned below, if necessary.

The term “cycloalkyl group” means a monocyclic or bicyclic monovalentsaturated hydrocarbon ring having 3 to 12 carbon atoms, and themonocyclic saturated hydrocarbon group having 3 to 7 carbon atoms ismore preferable. Examples thereof are a monocyclic alkyl group and abicyclic alkyl group such as cyclopropyl group, cyclobutyl group,cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctylgroup, cyclodecyl group, etc. These groups may optionally andindependently be substituted by 1 to 4 substituents as mentioned below,if necessary. The cycloalkyl group may optionally be condensed with asaturated hydrocarbon ring or an unsaturated hydrocarbon ring (saidsaturated hydrocarbon ring and unsaturated hydrocarbon ring mayoptionally contain an oxygen atom, a nitrogen atom, a sulfur atom, SO orSO₂ within the ring, if necessary), and the condensed saturatedhydrocarbon ring and the condensed unsaturated hydrocarbon ring may beoptionally and independently be substituted by 1 to 4 substituents asmentioned below.

The term “cycloalkylidene group” means a monocyclic or bicyclic divalentsaturated hydrocarbon ring having 3 to 12 carbon atoms, and themonocyclic saturated hydrocarbon group having 3 to 6 carbon atoms ispreferable. Examples thereof are a monocyclic alkylidene group and abicyclic alkylidene group such as cyclopropylidene group,cyclobutylidene group, cyclopentylidine group, cyclohexylidene group,etc. These groups may optionally and independently be substituted by 1to 4 substituents as mentioned below, if necessary. Besides, thecycloalkylidene group may optionally be condensed with a saturatedhydrocarbon ring or an unsaturated hydrocarbon ring (said saturatedhydrocarbon ring and unsaturated hydrocarbon ring may optionally containan oxygen atom, a nitrogen atom, a sulfur atom, SO or SO₂ within thering, if necessary), and the condensed saturated hydrocarbon ring andthe unsaturated hydrocarbon ring may be optionally and independently besubstituted by 1 to 4 substituents as mentioned below.

The term “cycloalkenyl group” means a monocyclic or bicyclic monovalentunsaturated hydrocarbon ring having 4 to 12 carbon atoms and having atleast one double bond. The preferable cycloalkenyl group is a monocyclicunsaturated hydrocarbon group having 4 to 7 carbon atoms. Examplesthereof are monocyclic alkenyl groups such as cyclopentenyl group,cyclopentadienyl group, cyclohexenyl group, etc. These groups mayoptionally and independently be substituted by 1 to 4 substituents asmentioned below, if necessary. Besides, the cycloalkenyl group mayoptionally be condensed with a saturated hydrocarbon ring or anunsaturated hydrocarbon ring (said saturated hydrocarbon ring andunsaturated hydrocarbon ring may optionally contain an oxygen atom, anitrogen atom, a sulfur atom, SO or SO₂ within the ring, if necessary),and the condensed saturated hydrocarbon ring and the unsaturatedhydrocarbon ring may be optionally and independently be substituted by 1to 4 substituents as mentioned below.

The term “cycloalkynyl group” means a monocyclic or bicyclic unsaturatedhydrocarbon ring having 6 to 12 carbon atoms, and having at least onetriple bond. The preferable cycloalkynyl group is a monocyclicunsaturated hydrocarbon group having 6 to 8 carbon atoms. Examplesthereof are monocyclic alkynyl groups such as cyclooctynyl group,cyclodecynyl group. These groups may optionally be substituted by 1 to 4substituents as mentioned below, if necessary. Besides, the cycloalkynylgroup may optionally and independently be condensed with a saturatedhydrocarbon ring or an unsaturated hydrocarbon ring (said saturatedhydrocarbon ring and unsaturated hydrocarbon ring may optionally containan oxygen atom, a nitrogen atom, a sulfur atom, SO or SO₂ within thering, if necessary), and the condensed saturated hydrocarbon ring or theunsaturated hydrocarbon ring may be optionally and independently besubstituted by 1 to 4 substituents as mentioned below.

The term “aryl group” means a monocyclic or bicyclic monovalent aromatichydrocarbon group having 6 to 10 carbon atoms. Examples thereof arephenyl group, naphthyl group (including 1-naphthyl group and 2-naphthylgroup). These groups may optionally and independently be substituted by1 to 4 substituents as mentioned below, if necessary. Besides, the arylgroup may optionally be condensed with a saturated hydrocarbon ring oran unsaturated hydrocarbon ring (said saturated hydrocarbon ring andunsaturated hydrocarbon ring may optionally contain an oxygen atom, anitrogen atom, a sulfur atom, SO or SO₂ within the ring, if necessary),and the condensed saturated hydrocarbon ring or the unsaturatedhydrocarbon ring may be optionally and independently be substituted by 1to 4 substituents as mentioned below.

The term “unsaturated monocyclic heterocyclic ring” means an unsaturatedhydrocarbon ring containing 1-4 heteroatoms independently selected froma nitrogen atom, an oxygen atom and a sulfur atom, and the preferableone is a 4- to 7-membered saturated or unsaturated hydrocarbon ringcontaining 1-4 heteroatoms independently selected from a nitrogen atom,an oxygen atom and a sulfur atom. Examples thereof are pyridine,pyrimidine, pyrazine, furan, thiophene, pyrrole, imidazole, pyrazole,oxazole, isoxazole, 4,5-dihydrooxazole, thiazole, isothiazole,thiadiazole, triazole, tetrazole, etc. Among them, pyridine, pyrimidine,pyrazine, furan, thiophene, pyrrole, imidazole, oxazole, and thiazolecan be preferably used. The “unsaturated monocyclic heterocyclic ring”may optionally and independently be substituted by 1-4 substituents asmentioned below, if necessary.

The term “unsaturated fused heterobicyclic ring” means hydrocarbon ringcomprised of a saturated or a unsaturated hydrocarbon ring condensedwith the above mentioned unsaturated monocyclic heterocyclic ring wheresaid saturated hydrocarbon ring and said unsaturated hydrocarbon ringmay optionally contain an oxygen atom, a nitrogen atom, a sulfur atom,SO, or SO₂ within the ring, if necessary. The “unsaturated fusedheterobicyclic ring” includes, for example, benzothiophene, indole,tetrahydrobenzothiophene, benzofuran, isoquinoline, thienothiophene,thienopyridine, quinoline, indoline, isoindoline, benzothiazole,benzoxazole, indazole, dihydro-isoquinoline, etc. Further, the“heterocyclic ring” also includes possible N- or S-oxides thereof.

The term “heterocyclyl” means a monovalent group of the above-mentionedunsaturated monocyclic heterocyclic ring or unsaturated fusedheterobicyclic ring and a monovalent group of the saturated version ofthe above-mentioned unsaturated monocyclic heterocyclic or unsaturatedfused heterobicyclic ring. If necessary, the heterocyclyl may optionallyand independently be substituted by 1 to 4 substituents as mentionedbelow.

The term “alkanoyl group” means a formyl group and ones formed bybinding an “alkyl group” to a carbonyl group.

The term “alkoxy group” means ones formed by binding an “alkyl group” toan oxygen atom.

The substituent for the above each group includes, for example, ahalogen atom (e.g., fluorine, chlorine, bromine, iodine), a nitro group,a cyano group, an oxo group, a hydroxy group, a mercapto group, acarboxyl group, a sulfo group, an alkyl group, an alkenyl group, analkynyl group, a cycloalkyl group, a cycloalkylidenemethyl group, acycloalkenyl group, a cycloalkynyl group, an aryl group, a heterocyclylgroup, an alkoxy group, an alkenyloxy group, an alkynyloxy group, acycloalkyloxy group, a cycloalkenyloxy group, a cycloalkynyloxy group,an aryloxy group, a heterocyclyloxy group, an alkanoyl group, analkenylcarbonyl group, an alkynylcarbonyl group, a cycloalkylcarbonylgroup, a cycloalkenylcarbonyl group, a cycloalkynylcarbonyl group, anarylcarbonyl group, a heterocyclylcarbonyl group, an alkoxycarbonylgroup, an alkenyloxycarbonyl group, an alkynyloxycarbonyl group, acycloalkyloxycarbonyl group, a cycloalkenyloxycarbonyl group, acycloalkynyloxycarbonyl group, an aryloxycarbonyl group, aheterocyclyloxycarbonyl group, an alkanoyloxy group, analkenylcarbonyloxy group, an alkynylcarbonyloxy group, acycloalkylcarbonyloxy group, a cycloalkenylcarbonyloxy group, acycloalkynylcarbonyloxy group, an arylcarbonyloxy group, aheterocyclylcarbonyloxy group, an alkylthio group, an alkenylthio group,an alkynylthio group, a cycloalkylthio group, a cycloalkenylthio group,a cycloalkynylthio group, an arylthio group, a heterocyclylthio group,an amino group, a mono- or di-alkylamino group, a mono- ordi-alkanoylamino group, a mono- or di-alkoxycarbonylamino group, a mono-or di-arylcarbonylamino group, an alkylsulfinylamino group, analkylsulfonylamino group, an arylsulfinylamino group, anarylsulfonylamino group, a carbamoyl group, a mono- or di-alkylcarbamoylgroup, a mono- or di-arylcarbamoyl group, an alkylsulfinyl group, analkenyl-sulfinyl group, an alkynylsulfinyl group, a cycloalkylsulfinylgroup, a cycloalkenylsulfinyl group, a cycloalkynylsulfinyl group, anarylsulfinyl group, a heterocyclylsulfinyl group, an alkylsulfonylgroup, an alkenylsulfonyl group, an alkynylsulfonyl group, acycloalkylsulfonyl group, a cyclo-alkenylsulfonyl group, acycloalkynylsulfonyl group, an aryl-sulfonyl group, and aheterocyclylsulfonyl group. Each group as mentioned above may optionallybe substituted by these substituents.

Further, the terms such as a haloalkyl group, a halo-lower alkyl group,a haloalkoxy group, a halo-lower alkoxy group, a halophenyl group, or ahaloheterocyclyl group mean an alkyl group, a lower alkyl group, analkoxy group, a lower alkoxy group, a phenyl group or a heterocyclylgroup (hereinafter, referred to as an alkyl group, etc.) beingsubstituted by one or more halogen atoms, respectively. Preferable onesare an alkyl group, etc. being substituted by 1 to 7 halogen atoms, andmore preferable ones are an alkyl group, etc. being substituted by 1 to5 halogen atoms. Similarly, the terms such as a hydroxyalkyl group, ahydroxy-lower alkyl group, a hydroxy-alkoxy group, a hydroxy-loweralkoxy group and a hydroxyphenyl group mean an alkyl group, etc., beingsubstituted by one or more hydroxy groups. Preferable ones are an alkylgroup, etc., being substituted by 1 to 4 hydroxy groups, and morepreferable ones are analkyl group, etc., being substituted by 1 to 2hydroxy groups. Further, the terms such as an alkoxyalkyl group, a loweralkoxyalkyl group, an alkoxy-lower alkyl group, a lower alkoxy-loweralkyl group, an alkoxyalkoxy group, a lower alkoxyalkoxy group, analkoxy-lower alkoxy group, a lower alkoxy-lower alkoxy group, analkoxyphenyl group, and a lower alkoxyphenyl group means an alkyl group,etc., being substituted by one or more alkoxy groups. Preferable onesare an alkyl group, etc., being substituted by 1 to 4 alkoxy groups, andmore preferable ones are an alkyl group, etc., being substituted by 1 to2 alkoxy groups.

The terms “arylakyl” and “arylalkoxy” as used alone or as part ofanother group refer to alkyl and alkoxy groups as described above havingan aryl substituent.

The term “lower” used in the definitions for the formulae in the presentspecification means a straight or branched carbon chain having 1 to 6carbon atoms, unless defined otherwise. More preferably, it means astraight or branched carbon chain having 1 to 4 carbon atoms.

The term “prodrug” means an ester or carbonate, which is formed byreacting one or more hydroxy groups of the compound of the formula Iwith an acylating agent substituted by an alkyl, an alkoxy or an aryl bya conventional method to produce acetate, pivalate, methylcarbonate,benzoate, etc. Further, the prodrug includes also an ester or amide,which is similarly formed by reacting one or more hydroxy groups of thecompound of the formula I with an α-amino acid or a β-amino acid, etc.using a condensing agent by a conventional method.

The pharmaceutically acceptable salt of the compound of the formula Iincludes, for example, a salt with an alkali metal such as lithium,sodium, potassium, etc.; a salt with an alkaline earth metal such ascalcium, magnesium, etc.; a salt with zinc or aluminum; a salt with anorganic base such as ammonium, choline, diethanolamine, lysine,ethylenediamine, t-butylamine, t-octylamine,tris(hydroxymethyl)aminomethane, N-methyl glucosamine, triethanolamineand dehydroabietylamine; a salt with an inorganic acid such ashydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid,nitric acid, phosphoric acid, etc.; or a salt with an organic acid suchas formic acid, acetic acid, propionic acid, oxalic acid, malonic acid,succinic acid, fumaric acid, maleic acid, lactic acid, malic acid,tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid,benzenesulfonic acid, etc.; or a salt with an acidic amino acid such asaspartic acid, glutamic acid, etc.

The compound of the present invention also includes a mixture ofstereoisomers, or each pure or substantially pure isomer. For example,the present compound may optionally have one or more asymmetric centersat a carbon atom containing any one of substituents. Therefore, thecompound of the formula I may exist in the form of enantiomer ordiastereomer, or a mixture thereof. When the present compound (I)contains a double bond, the present compound may exist in the form ofgeometric isomerism (cis-compound, trans-compound), and when the presentcompound (I) contains an unsaturated bond such as carbonyl, then thepresent compound may exist in the form of a tautomer, and the presentcompound also includes these isomers or a mixture thereof. The startingcompound in the form of a racemic mixture, enantiomer or diastereomermay be used in the processes for preparing the present compound. Whenthe present compound is obtained in the form of a diastereomer orenantiomer, they can be separated by a conventional method such aschromatography or fractional crystallization.

In addition, the present compound (I) includes an intramolecular salt,hydrate, solvate or polymorphism thereof.

Examples of the optionally substituted unsaturated monocyclicheterocyclic ring of the present invention include an unsaturatedmonocyclic heterocyclic ring which may optionally be substituted by 1-5substituents selected from the group consisting of a halogen atom, anitro group, a cyano group, an oxo group, a hydroxyl group, a mercaptogroup, a carboxyl group, a sulfo group, an alkyl group, an alkenylgroup, an alkynyl group, a cycloalkyl group, a cycloalkylidenemethylgroup, a cycloalkenyl group, a cycloalkynyl group, an aryl group, aheterocyclyl group, an alkoxy group, an alkenyloxy group, an alkynyloxygroup, a cycloalkyloxy group, a cycloalkenyloxy group, a cycloalkynyloxygroup, an aryloxy group, a hetero-cyclyloxy group, an alkanoyl group, analkenylcarbonyl group, an alkynylcarbonyl group, a cycloalkylcarbonylgroup, a cycloalkenylcarbonyl group, a cycloalkynylcarbonyl group, anarylcarbonyl group, a heterocyclylcarbonyl group, an alkoxycarbonylgroup, an alkenyloxycarbonyl group, an alkynyloxycarbonyl group, acycloalkyloxycarbonyl group, a cycloalkenyloxycarbonyl group, acycloalkynyloxycarbonyl group, an aryloxycarbonyl group, aheterocyclyloxycarbonyl group, an alkanoyloxy group, analkenylcarbonyloxy group, an alkynylcarbonyloxy group, acycloalkylcarbonyloxy group, a cycloalkenylcarbonyloxy group, acycloalkynylcarbonyloxy group, an arylcarbonyloxy group, aheterocyclylcarbonyloxy group, an alkylthio group, an alkenylthio group,an alkynylthio group, a cycloalkylthio group, a cycloalkenylthio group,a cycloalkynylthio group, an arylthio group, a heterocyclylthio group,an amino group, a mono- or di-alkylamino group, a mono- ordi-alkanoylamino group, a mono- or di-alkoxycarbonylamino group, a mono-or di-arylcarbonylamino group, an alkylsulfinylamino group, analkylsulfonylamino group, an arylsulfinylamino group, anarylsulfonylamino group, a carbamoyl group, a mono- or di-alkylcarbamoylgroup, a mono- or di-arylcarbamoyl group, an alkylsulfinyl group, analkenyl-sulfinyl group, an alkynylsulfinyl group, a cycloalkylsulfinylgroup, a cycloalkenylsulfinyl group, a cycloalkynylsulfinyl group, anarylsulfinyl group, a heterocyclylsulfinyl group, an alkylsulfonylgroup, an alkenylsulfonyl group, an alkynylsulfonyl group, acycloalkylsulfonyl group, a cycloalkenylsulfonyl group, acycloalkynylsulfonyl group, an arylsulfonyl group, and aheterocyclylsulfonyl group wherein each substituent may optionally befurther substituted by these substituents.

Examples of the optionally substituted unsaturated fused heterobicyclicring of the present invention include an unsaturated fusedheterobicyclic ring which may optionally be substituted by 1-5substituents selected from the group consisting of a halogen atom, anitro group, a cyano group, an oxo group, a hydroxy group, a mercaptogroup, a carboxyl group, a sulfo group, an alkyl group, an alkenylgroup, an alkynyl group, a cycloalkyl group, a cycloalkylidene-methylgroup, a cycloalkenyl group, a cycloalkynyl group, an aryl group, aheterocyclyl group, an alkoxy group, an alkenyloxy group, an alkynyloxygroup, a cycloalkyloxy group, a cycloalkenyloxy group, a cycloalkynyloxygroup, an aryloxy group, a heterocyclyloxy group, an alkanoyl group, analkenylcarbonyl group, an alkynylcarbonyl group, a cycloalkylcarbonylgroup, a cycloalkenyl-carbonyl group, a cycloalkynyl-carbonyl group, anarylcarbonyl group, a heterocyclylcarbonyl group, an alkoxycarbonylgroup, an alkenyloxycarbonyl group, an alkynyloxy-carbonyl group, acycloalkyloxycarbonyl group, a cycloalkenyloxy-carbonyl group, acycloalkynyloxycarbonyl group, an aryloxycarbonyl group, aheterocyclyloxycarbonyl group, an alkanoyloxy group, analkenylcarbonyloxy group, an alkynylcarbonyloxy group, acyclo-alkylcarbonyloxy group, a cycloalkenylcarbonyloxy group, acyclo-alkynylcarbonyloxy group, an arylcarbonyloxy group, aheterocyclyl-carbonyloxy group, an alkylthio group, an alkenylthiogroup, an alkynylthio group, a cycloalkylthio group, a cycloalkenylthiogroup, a cycloalkynylthio group, an arylthio group, a heterocyclylthiogroup, an amino group, a mono- or di-alkylamino group, a mono- ordi-alkanoyl-amino group, a mono- or di-alkoxycarbonylamino group, amono- or di-arylcarbonylamino group, an alkylsulfinylamino group, analkyl-sulfonylamino group, an arylsulfinylamino group, anarylsulfonylamino group, a carbamoyl group, a mono- or di-alkylcarbamoylgroup, a mono- or di-arylcarbamoyl group, an alkylsulfinyl group, analkenylsulfinyl group, an alkynylsulfinyl group, a cycloalkylsulfinylgroup, a cyclo-alkenylsulfinyl group, a cycloalkynylsulfinyl group, anarylsulfinyl group, a heterocyclylsulfinyl group, an alkylsulfonylgroup, an alkenylsulfonyl group, an alkynylsulfonyl group, acycloalkylsulfonyl group, a cyclo-alkenylsulfonyl group, acycloalkynylsulfonyl group, an arylsulfonyl group, and aheterocyclylsulfonyl group, wherein each substituent may optionally befurther substituted by these substituents.

Examples of the optionally substituted benzene ring of the presentinvention include a benzene ring which may optionally be substituted by1-5 substituents selected from the group consisting of a halogen atom, anitro group, a cyano group, a hydroxy group, a mercapto group, acarboxyl group, a sulfo group, an alkyl group, an alkenyl group, analkynyl group, a cycloalkyl group, a cycloalkylidenemethyl group, acycloalkenyl group, a cycloalkynyl group, an aryl group, a heterocyclylgroup, an alkoxy group, an alkenyloxy group, an alkynyloxy group, acycloalkyloxy group, a cycloalkenyloxy group, a cycloalkynyloxy group,an aryloxy group, a heterocyclyloxy group, an alkanoyl group, analkenylcarbonyl group, an alkynylcarbonyl group, a cycloalkylcarbonylgroup, a cycloalkenylcarbonyl group, a cycloalkynylcarbonyl group, anarylcarbonyl group, a heterocyclylcarbonyl group, an alkoxycarbonylgroup, an alkenyloxycarbonyl group, an alkynyloxycarbonyl group, acycloalkyloxycarbonyl group, a cycloalkenyloxycarbonyl group, acycloalkynyloxycarbonyl group, an aryloxycarbonyl group, aheterocyclyloxycarbonyl group, an alkanoyloxy group, analkenylcarbonyloxy group, an alkynylcarbonyloxy group, acycloalkylcarbonyloxy group, a cycloalkenylcarbonyloxy group, acycloalkynylcarbonyloxy group, an arylcarbonyloxy group, aheterocyclylcarbonyloxy group, an alkylthio group, an alkenylthio group,an alkynylthio group, a cycloalkylthio group, a cycloalkenylthio group,a cycloalkynylthio group, an arylthio group, a heterocyclylthio group,an amino group, a mono- or di-alkylamino group, a mono- ordi-alkanoylamino group, a mono- or di-alkoxycarbonylamino group, a mono-or di-arylcarbonylamino group, an alkylsulfinylamino group, analkylsulfonylamino group, an arylsulfinylamino group, anarylsulfonylamino group, a carbamoyl group, a mono- or di-alkylcarbamoylgroup, a mono- or di-arylcarbamoyl group, an alkylsulfinyl group, analkenylsulfinyl group, an alkynylsulfinyl group, a cycloalkylsulfinylgroup, a cycloalkenylsulfinyl group, a cycloalkynylsulfinyl group, anarylsulfinyl group, a heterocyclylsulfinyl group, an alkylsulfonylgroup, an alkenylsulfonyl group, an alkynylsulfonyl group, acycloalkylsulfonyl group, a cycloalkenylsulfonyl group, acycloalkynylsulfonyl group, an arylsulfonyl group, aheterocyclylsulfonyl group, an alkylene group, an alkyleneoxy group, analkylenedioxy group, and an alkenylene group wherein each substituentmay optionally be further substituted by these substituents. Moreover,examples of the optionally substituted benzene ring include a benzenering substituted with an alkylene group to form an annelated carbocycletogether with the carbon atoms to which they are attached, and alsoincludes a benzene ring substituted with an alkenylene group to form anannelated carbocycle such as a fused benzene ring together with thecarbon atoms to which they are attached.

Preferable examples of the optionally substituted unsaturated monocyclicheterocyclic ring include an unsaturated monocyclic heterocyclic ringwhich may optionally be substituted by 1-3 substituents selected fromthe group consisting of a halogen atom, a hydroxy group, an alkoxygroup, an alkyl group, a haloalkyl group, a haloalkoxy group, ahydroxyalkyl group, an alkoxyalkyl group, an alkoxyalkoxy group, analkenyl group, an alkynyl group, a cycloalkyl group, acycloalkylidenemethyl group, a cycloalkenyl group, a cycloalkyloxygroup, an aryl group, an aryloxy group, an arylalkoxy group, a cyanogroup, a nitro group, an amino group, a mono- or di-alkylamino group, analkanoylamino group, an alkoxycarbonylamino group, a carboxyl group, analkoxycarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoylgroup, an alkanoyl group, an alkylsulfonylamino group, anarylsulfonylamino group, an alkylsulfinyl group, an alkylsulfonyl group,an arylsulfonyl group, a heterocyclyl group, and an oxo group.

Preferable examples of the optionally substituted unsaturated fusedheterobicyclic ring include an unsaturated fused heterobicyclic ringwhich may optionally be substituted by 1-3 substituents independentlyselected from the group consisting of a halogen atom, a hydroxy group,an alkoxy group, an alkyl group, a haloalkyl group, a haloalkoxy group,a hydroxyalkyl group, an alkoxyalkyl group, an alkoxyalkoxy group, analkenyl group, an alkynyl group, a cycloalkyl group, acycloalkylidenemethyl group, a cycloalkenyl group, a cyclo-alkyloxygroup, an aryl group, an aryloxy group, an arylalkoxy group, a cyanogroup, a nitro group, an amino group, a mono- or di-alkylamino group, analkanoylamino group, an alkoxycarbonylamino group, a carboxyl group, analkoxycarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoylgroup, an alkanoyl group, an alkylsulfonylamino group, anarylsulfonylamino group, an alkylsulfinyl group, an alkylsulfonyl group,an arylsulfonyl group, a heterocyclyl group, and an oxo group.

Preferable examples of the optionally substituted benzene ring include abenzene ring which may optionally be substituted by 1-3 substituentsselected from the group consisting of a halogen atom, a hydroxy group,an alkoxy group, an alkyl group, a haloalkyl group, a haloalkoxy group,a hydroxyalkyl group, an alkoxyalkyl group, an alkoxyalkoxy group, analkenyl group, an alkynyl group, a cycloalkyl group, acycloalkylidenemethyl group, a cycloalkenyl group, a cycloalkyloxygroup, an aryl group, an aryloxy group, an arylalkoxy group, a cyanogroup, a nitro group, an amino group, a mono- or di-alkylamino group, analkanoylamino group, an alkoxycarbonylamino group, a carboxyl group, analkoxycarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoylgroup, an alkanoyl group, an alkylsulfonylamino group, anarylsulfonylamino group, an alkylsulfinyl group, an alkylsulfonyl group,an arylsulfonyl group, a heterocyclyl group, an alkylene group, analkyleneoxy group, an alkylenedioxy group, and an alkenylene group.

In another preferable embodiment of the present invention, theoptionally substituted unsaturated monocyclic heterocyclic ring is anunsaturated monocyclic heterocyclic ring which may optionally besubstituted by 1-3 substituents, independently selected from the groupconsisting of a halogen atom, a hydroxy group, a cyano group, a nitrogroup, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkylgroup, a cycloalkylidenemethyl group, an alkoxy group, an alkanoylgroup, an alkylthio group, an alkylsulfonyl group, an alkylsulfinylgroup, an amino group, a mono- or di-alkylamino group, an alkanoylaminogroup, an alkoxycarbonylamino group, a sulfamoyl group, a mono- ordi-alkylsulfamoyl group, a carboxyl group, an alkoxycarbonyl group, acarbamoyl group, a mono- or di-alkylcarbamoyl group, analkylsufonylamino group, a phenyl group, a phenoxy group, aphenylsulfonylamino group, a phenylsulfonyl group, a heterocyclyl group,and an oxo group;

the optionally substituted unsaturated fused heterobicyclic ring is anunsaturated fused heterobicyclic ring which may optionally besubstituted by 1-3 substituents selected from the group consisting of ahalogen atom, a hydroxy group, a cyano group, a nitro group, an alkylgroup, an alkenyl group, an alkynyl group, a cycloalkyl group, acycloalkylidenemethyl group, an alkoxy group, an alkylthio group, analkylsulfonyl group, an alkylsulfinyl group, an amino group, a mono- ordi-alkylamino group, an alkanoylamino group, an alkoxycarbonylaminogroup, a sulfamoyl group, a mono- or di-alkyl-sulfamoyl group, acarboxyl group, an alkoxycarbonyl group, a carbamoyl group, a mono- ordi-alkylcarbamoyl group, an alkanoyl group, an alkylsulfonylamino group,a phenyl group, a phenoxy group, a phenylsulfonylamino group,phenylsulfonyl group, a heterocyclyl group, and an oxo group; and

the optionally substituted benzene ring is a benzene ring which mayoptionally be substituted by 1-3 substituents, independently selectedfrom the group consisting of a halogen atom, a hydroxy group, a cyanogroup, a nitro group, an alkyl group, an alkenyl group, an alkynylgroup, a cycloalkyl group, a cycloalkylidenemethyl group, an alkoxygroup, an alkanoyl group, an alkylthio group, an alkylsulfonyl group, analklsulfinyl group, an amino group, a mono- or di-alkylamino group, analkanoylamino group, an alkoxycarbonylamino group, a sulfamoyl group, amono- or di-alkylsulfamoyl group, a carboxyl group, an alkoxycarbonylgroup, a carbamoyl group, a mono- or di-alkylcarbamoyl group, analkylsufonylamino group, a phenyl group, a phenoxy group, aphenylsulfonylamino group, a phenylsulfonyl group, a heterocyclyl group,an alkylene group, and an alkenylene group;

wherein each of the above-mentioned substituents on the unsaturatedmonocyclic heterocyclic ring, the unsaturated fused heterobicyclic ringand the benzene ring may further be substituted by 1-3 substituents,independently selected from the group consisting of a halogen atom, ahydroxy group, a cyano group, an alkyl group, a haloalkyl group, analkoxy group, a haloalkoxy group, an alkanoyl group, an alkylthio group,an alkylsulfonyl group, a mono- or di-alkylamino group, a carboxylgroup, an alkoxycarbonyl group, a phenyl group, an alkyleneoxy group, analkylenedioxy group, an oxo group, a carbamoyl group, and a mono- ordi-alkylcarbamoyl group.

In a preferable embodiment, the optionally substituted unsaturatedmonocyclic heterocyclic ring is an unsaturated monocyclic heterocyclicring which may optionally be substituted by 1-3 substituents,independently selected from the group consisting of a halogen atom, acyano group, an alkyl group, an alkoxy group, an alkanoyl group, a mono-or di-alkylamino group, an alkanoylamino group, an alkoxycarbonylaminogroup, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, amono- or di-alkylcarbamoyl group, a phenyl group, a heterocyclyl group,and an oxo group;

the optionally substituted unsaturated fused heterobicyclic ring is anunsaturated fused heterobicyclic ring which may optionally besubstituted by 1-3 substituents independently selected from the groupconsisting of a halogen atom, a cyano group, an alkyl group, an alkoxygroup, an alkanoyl group, a mono- or di-alkylamino group, analkanoylamino group, an alkoxycarbonylamino group, a carboxy group, analkoxycarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoylgroup, a phenyl group, a heterocyclyl group, and an oxo group; and

the optionally substituted benzene ring is a benzene ring which mayoptionally be substituted by 1-3 substituents, independently selectedfrom the group consisting of a halogen atom, a cyano group, an alkylgroup, analkoxy group, an alkanoyl group, a mono- or di-alkylaminogroup, an alkanoylamino group, an alkoxycarbonylamino group, a carboxylgroup, an alkoxycarbonyl group, a carbamoyl group, a mono- ordi-alkylcarbamoyl group, a phenyl group, a heterocyclyl group, analkylene group, and an alkenylene group;

wherein each of the above-mentioned substituents on the unsaturatedmonocyclic heterocyclic ring, the unsaturated fused heterobicyclic ringand the benzene ring may further be substituted by 1-3 substituents,independently selected from the group consisting of a halogen atom, acyano group, an alkyl group, a haloalkyl group, an alkoxy group, ahaloalkoxy group, an alkanoyl group, a mono- or di-alkylamino group, acarboxyl group, a hydroxy group, a phenyl group, an alkylenedioxy group,an alkyleneoxy group, an alkoxycarbonyl group, a carbamoyl group and amono- or di-alkylcarbamoyl group.

In another preferable embodiment,

-   (1) Ring A is an unsaturated monocyclic heterocyclic ring which may    optionally be substituted by 1-3 substituents, independently    selected from the group consisting of a halogen atom, a hydroxy    group, a cyano group, a nitro group, an alkyl group, an alkenyl    group, an alkynyl group, a cycloalkyl group, a cycloalkylidenemethyl    group, an alkoxy group, an alkanoyl group, an alkylthio group, an    alkylsulfonyl group, an alkl-sulfinyl group, an amino group, a mono-    or di-alkylamino group, a sulfamoyl group, a mono- or    di-alkylsulfamoyl group, a carboxyl group, an alkoxycarbonyl group,    a carbamoyl group, a mono- or di-alkylcarbamoyl group, an    alkylsufonylamino group, a phenyl group, a phenoxy group, a    phenylsulfonylamino group, a phenylsulfonyl group, a heterocyclyl    group, and an oxo group, and

Ring B is an unsaturated monocyclic heterocyclic ring, an unsaturatedfused heterobicyclic ring, or a benzene ring, each of which mayoptionally be substituted by 1-3 substituents, independently selectedfrom the group consisting of a halogen atom, a hydroxy group, a cyanogroup, a nitro group, an alkyl group, an alkenyl group, an alkynylgroup, a cycloalkyl group, a cycloalkylidenemethyl group, an alkoxygroup, an alkanoyl group, an alkylthio group, an alkylsulfonyl group, analkylsulfinyl group, an amino group, a mono- or di-alkylamino group, asulfamoyl group, a mono- or di-alkylsulfamoyl group, a carboxyl group,an alkoxycarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoylgroup, an alkylsufonylamino group, a phenyl group, a phenoxy group, aphenylsulfonylamino group, a phenylsulfonyl group, a heterocyclyl group,an alkylene group, and an alkenylene group;

-   (2) Ring A is a benzene ring which may optionally be substituted by    1-3 substituents, independently selected from the group consisting    of a halogen atom, a hydroxy group, a cyano group, a nitro group, an    alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group,    a cycloalkylidenemethyl group, an alkoxy group, an alkanoyl group,    an alkylthio group, an alkylsulfonyl group, an alklsulfinyl group,    an amino group, a mono- or di-alkylamino group, an alkanoylamino    group, a sulfamoyl group, a mono- or di-alkylsulfamoyl group, a    carboxyl group, an alkoxycarbonyl group, a carbamoyl group, a mono-    or di-alkylcarbamoyl group, an alkylsufonylamino group, a phenyl    group, a phenoxy group, a phenylsulfonylamino group, a    phenylsulfonyl group, a heterocyclyl group, an alkylene group, and    an alkenylene group, and

Ring B is an unsaturated monocyclic heterocyclic ring or an unsaturatedfused heterobicyclic ring, each of which may optionally be substitutedby 1-3 substituents, independently selected from the group consisting ofa halogen atom, a hydroxy group, a cyano group, a nitro group, an alkylgroup, an alkenyl group, an alkynyl group, a cycloalkyl group, acycloalkylidenemethyl group, an alkoxy group, an alkanoyl group, analkylthio group, an alkylsulfonyl group, an alklsulfinyl group, an aminogroup, a mono- or di-alkylamino group, a sulfamoyl group, a mono- ordi-alkylsulfamoyl group, a carboxyl group, an alkoxycarbonyl group, acarbamoyl group, a mono- or di-alkylcarbamoyl group, analkylsufonylamino group, a phenyl group, a phenoxy group, aphenylsulfonylamino group, a phenylsulfonyl group, a heterocyclyl group,an alkylene group and an oxo group; or

-   (3) Ring A is an unsaturated fused heterobicyclic ring which may    optionally be substituted by 1-3 substituents, independently    selected from the group consisting of a halogen atom, a hydroxy    group, a cyano group, a nitro group, an alkyl group, an alkenyl    group, an alkynyl group, a cycloalkyl group, a cycloalkylidenemethyl    group, an alkoxy group, an alkanoyl group, an alkylthio group, an    alkylsulfonyl group, an alkl-sulfinyl group, an amino group, a mono-    or di-alkylamino group, a sulfamoyl group, a mono- or    di-alkylsulfamoyl group, a carboxyl group, an alkoxycarbonyl group,    a carbamoyl group, a mono- or di-alkylcarbamoyl group, an    alkylsufonylamino group, a phenyl group, a phenoxy group, a    phenylsulfonylamino group, a phenylsulfonyl group, a heterocyclyl    group, and an oxo group, and

Ring B is an unsaturated monocyclic heterocyclic ring, an unsaturatedfused heterobicyclic ring, or a benzene ring, each of which mayoptionally be substituted by 1-3 substituents, independently selectedfrom the group consisting of a halogen atom, a hydroxy group, a cyanogroup, a nitro group, an alkyl group, an alkenyl group, an alkynylgroup, a cycloalkyl group, a cycloalkylidenemethyl group, an alkoxygroup, an alkanoyl group, an alkylthio group, an alkylsulfonyl group, analkl-sulfinyl group, an amino group, a mono- or di-alkylamino group, asulfamoyl group, a mono- or di-alkylsulfamoyl group, a carboxyl group,an alkoxycarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoylgroup, an alkylsufonylamino group, a phenyl group, a phenoxy group, aphenylsulfonylamino group, a phenylsulfonyl group, a heterocyclyl group,an alkylene group and an oxo group;

wherein each of the above-mentioned substituents on Ring A and Ring Bmay optionally be substituted by 1-3 substituents, independentlyselected from the group consisting of a halogen atom, a cyano group, analkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, analkanoyl group, a mono- or di-alkylamino group, a carboxyl group, ahydroxy group, a phenyl group, an alkylenedioxy group, an alkyleneoxygroup, an alkoxycarbonyl group, a carbamoyl group and a mono- ordi-alkylcarbamoyl group.

In a more preferable embodiment of the present invention, Ring A andRing B are

-   (1) Ring A is an unsaturated monocyclic heterocyclic ring which may    optionally be substituted by a halogen atom, a lower alkyl group, a    halo-lower alkyl group, a lower alkoxy group, or an oxo group, and    Ring B is (a) a benzene ring which may optionally be substituted by    a halogen atom; a cyano group; a lower alkyl group; a halo-lower    alkyl group; a lower alkoxy group; a halo-lower alkoxy group; a    mono- or di-lower alkylamino group; a phenyl group optionally    substituted by a halogen atom, a cyano group, a lower alkyl group, a    halo-lower alkyl group, a lower alkoxy group, or a mono- or di-lower    alkylamino group; or a heterocyclyl group optionally substituted by    a halogen atom, a cyano group, a lower alkyl group, a halo-lower    alkyl group, a lower alkoxy group, or a mono- or di-lower alkylamino    group; (b) an unsaturated monocyclic heterocyclic ring which may    optionally be substituted by a group selected from a halogen atom,    cyano group, a lower alkyl group, a halo-lower alkyl group, a lower    alkoxy group, a halo-lower alkoxy group, a mo- or di-lower    alkylamino group, a phenyl group which may be substituted with a    halogen atom, cyano group, a lower alkyl group, a halo-lower alkyl    group, a lower alkoxy group, or a mono- or di-lower alkylamino    group; and a heterocyclyl group which may optionally be substituted    with a group selected from a halogen atom, cyano group, a lower    alkyl group, a halo-lower alkyl group, a lower alkoxy group, or a    mono- or di-lower alkylamino group; or (c) an unsaturated fused    heterobicyclic ring which may optionally be substituted by a group    selected from a halogen atom, cyano group, a lower alkyl group, a    halo-lower alkyl group, a lower alkoxy group, a halo-lower alkoxy    group, a mono- or di-lower alkylamino group, a phenyl group which    may be substituted with a halogen atom, cyano group, a lower alkyl    group, a halo-lower alkyl group, a lower alkoxy group, or a mono- or    di-lower alkylamino group; and a heterocyclyl group which may    optionally be substituted with a group selected from a halogen atom,    cyano group, a lower alkyl group, a halo-lower alkyl group, a lower    alkoxy group, or a mono- or di-lower alkylamino group;-   (2) Ring A is a benzene ring which may optionally be substituted by    a halogen atom, a lower alkyl group, a halo-lower alkyl group, a    lower alkoxy group, a phenyl group, or a lower alkenylene group, and    Ring B is (a) an unsaturated monocyclic heterocyclic ring which may    optionally be substituted by a halogen atom; a cyano group; a lower    alkyl group; a halo-lower alkyl group; a phenyl-lower alkyl group; a    lower alkoxy group; a halo-lower alkoxy group; a mono- or di-lower    alkylamino group; a phenyl group optionally substituted by a halogen    atom, a cyano group, a lower alkyl group, a halo-lower alkyl group,    a lower alkoxy group, a mono- or di-lower alkylamino group, or a    carbamoyl group; or a heterocyclyl group optionally substituted by a    halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl    group, a lower alkoxy group, a mono- or di-lower alkylamino group or    a carbamoyl group; (b) an unsaturated fused heterobicyclic ring    which may optionally be substituted by a group selected from a    halogen atom, cyano group, a lower alkyl group, a halo-lower alkyl    group, a phenyl-lower alkyl group, a lower alkoxy group, a    halo-lower alkoxy group, a mo- or di-lower alkylamino group, a    phenyl group which may be substituted with a halogen atom, cyano    group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy    group, or a mono- or di-lower alkylamino group; and a heterocyclyl    group which may optionally be substituted with a group selected from    a halogen atom, cyano group, a lower alkyl group, a halo-lower alkyl    group, a lower alkoxy group, or a mono- or di-lower alkylamino    group; or-   (3) Ring A is an unsaturated fused heterobicyclic ring which may    optionally be substituted by a halogen atom, a lower alkyl group, a    halo-lower alkyl group, a lower alkoxy group, or an oxo group, and    Ring B is (a) a benzene ring which may optionally be substituted by    a group selected from a halogen atom, cyano group, a lower alkyl    group, a halo-lower alkyl group, a lower alkoxy group, a halo-lower    alkoxy group, a mo- or di-lower alkylamino group, a phenyl group    which may be substituted with a halogen atom, cyano group, a lower    alkyl group, a halo-lower alkyl group, a lower alkoxy group, or a    mono- or di-lower alkylamino group; and a heterocyclyl group which    may optionally be substituted with a group selected from a halogen    atom, cyano group, a lower alkyl group, a halo-lower alkyl group, a    lower alkoxy group, or a mono- or di-lower alkylamino group; (b) an    unsaturated monocyclic heterocyclic ring which may optionally be    substituted by a halogen atom; a cyano group; a lower alkyl group; a    halo-lower alkyl group; a lower alkoxy group; a halo-lower alkoxy    group; a mono- or di-lower alkylamino group; a phenyl group    optionally substituted by a halogen atom, a cyano group, a lower    alkyl group, a halo-lower alkyl group, a lower alkoxy group, or a    mono- or di-lower alkylamino group; or a heterocyclyl group    optionally substituted by a halogen atom, a cyano group, a lower    alkyl group, a halo-lower alkyl group, a lower alkoxy group, or a    mono- or di-lower alkylamino group; or (c) an unsaturated fused    heterobicyclic ring which may optionally be substituted by a group    selected from a halogen atom, cyano group, a lower alkyl group, a    halo-lower alkyl group, a lower alkoxy group, a halo-lower alkoxy    group, a mo- or di-lower alkylamino group, a phenyl group which may    be substituted with a halogen atom, cyano group, a lower alkyl    group, a halo-lower alkyl group, a lower alkoxy group, or a mono- or    di-lower alkylamino group; and a heterocyclyl group which may    optionally be substituted with a group selected from a halogen atom,    cyano group, a lower alkyl group, a halo-lower alkyl group, a lower    alkoxy group, or a mono- or di-lower alkylamino group.

In another more preferable embodiment, Y is —CH₂— and is linked at the3-position of Ring A, with respect to X being the 1-position, Ring A isa benzene ring which is substituted by 1-3 substituents selected fromthe group consisting of a lower alkyl group, a halo-lower alkyl group, ahalogen atom, a lower alkoxy group, a phenyl group, and a loweralkenylene group, and Ring B is an unsaturated monocyclic heterocyclicring or an unsaturated fused heterobicyclic ring, each of which may besubstituted by 1-3 substituents selected from the group consisting of alower alkyl group, a halo-lower alkyl group, a phenyl-lower alkyl group,a halogen atom, a lower alkoxy group, a halo-lower alkoxy group, aphenyl group, a halophenyl group, a cyanophenyl group, a loweralkylphenyl group, a halo-lower alkylphenyl group, a lower alkoxyphenylgroup, a halo-lower alkoxy phenyl group, a lower alkylenedioxyphenylgroup, a lower alkyleneoxy phenyl group, a mono- or di-loweralkylaminophenyl group, a carbamoyl phenyl group, a mono- or di-loweralkylcarbamoylphenyl group, a heterocyclyl group, a haloheterocyclylgroup, a cyanoheterocyclyl group, a lower alkylheterocyclyl group, alower alkoxyheterocyclyl group, a mono- or di-loweralkylaminoheterocycyclyl group, a carbamoylheterocyclyl group, and amono- or di-lower alkylcarbamoyl group.

In another more preferable embodiment, Y is —CH₂— and is linked at the3-position of Ring A, with respect to X being the 1-position, Ring A isan unsaturated monocyclic heterocyclic ring which may be substituted by1-3 substituents selected from the group consisting of a lower alkylgroup, a halogen atom, a lower alkoxy group, and an oxo group, and RingB is a benzene ring which may be substituted by 1-3 substituentsselected from the group consisting of a lower alkyl group, a halo-loweralkyl group, a halogen atom, a lower alkoxy group, a halo-lower alkoxygroup, a phenyl group, a halophenyl group, a cyanophenyl group, a loweralkylphenyl group, a halo-lower alkylphenyl group, a lower alkoxyphenylgroup, a heterocyclyl group, a haloheterocyclyl group, acyanoheterocyclyl group, a lower alkylheterocyclyl group, and a loweralkoxyheterocyclyl group.

Further, in another preferable embodiment, Y is —CH₂— and is linked atthe 3-position of Ring A, with respect to X being the 1-position, Ring Ais an unsaturated monocyclic heterocyclic ring which may be substitutedby 1-3 substituents selected from the group consisting of a lower alkylgroup, a halogen atom, a lower alkoxy group, and an oxo group, and RingB is an unsaturated monocyclic heterocyclic ring or an unsaturated fusedheterobicyclic ring, each of which may be substituted by 1-3substituents selected from the group consisting of a lower alkyl group,a halo-lower alkyl group, a halogen atom, a lower alkoxy group, ahalo-lower alkoxy group, a phenyl group, a halophenyl group, acyanophenyl group, a lower alkylphenyl group, a halo-lower alkylphenylgroup, a lower alkoxyphenyl group, a halo-lower alkoxyphenyl group, aheterocyclyl group, a haloheterocyclyl group, a cyanoheterocyclyl group,a lower alkylheterocyclyl group, and a lower alkoxyheterocyclyl group.In a more preferable embodiment of the present invention, X is a carbonatom and Y is —CH₂—.

Further, in another preferable embodiment, Ring A and Ring B are

-   (1) Ring A is a benzene ring which may optionally be substituted by    1-3 substituents, independently selected from the group consisting    of a halogen atom, a lower alkyl group optionally substituted by a    halogen atom or a lower alkoxy group, a lower alkoxy group    optionally substituted by a halogen atom or a lower alkoxy group, a    cycloalkyl group, a cycloalkoxy group, a phenyl group, and a lower    alkenylene group, and    Ring B is an unsaturated monocyclic heterocyclic ring or an    unsaturated fused heterobicyclic ring, each of which may optionally    be substituted by 1-3 substituents, independently selected from the    group consisting of a halogen atom; a lower alkyl group optionally    substituted by a halogen atom, a lower alkoxy group or a phenyl    group; a lower alkoxy group optionally substituted by a halogen atom    or a lower alkoxy group; a cycloalkyl group; a cycloalkoxy group; a    phenyl group optionally substituted by a halogen atom, a cyano    group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy    group, a halo-lower alkoxy group, or a carbamoyl group; a    heterocyclyl group optionally substituted by a halogen atom, a cyano    group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy    group, a halo-lower alkoxy group or a carbamoyl roup; and an oxo    group,-   (2) Ring A is an unsaturated monocyclic heterocyclic ring which may    optionally be substituted by 1-3 substituents, independently    selected from the group consisting of a halogen atom, a lower alkyl    group optionally substituted by a lower alkoxy group, a lower alkoxy    group optionally substituted by a halogen atom or a lower alkoxy    group, a cycloalkyl group, a cycloalkoxy group, and an oxo group,    and    Ring B is a benzene ring which may optionally be substituted by 1-3    substituents, independently selected from the group consisting of a    halogen atom; a lower alkyl group optionally substituted by a    halogen atom, a lower alkoxy group or a phenyl group; a lower alkoxy    group optionally substituted by a halogen atom or a lower alkoxy    group; a cycloalkyl group; a cycloalkoxy group; a phenyl group    optionally substituted by a halogen atom, a cyano group, a lower    alkyl group, a halo-lower alkyl group, a lower alkoxy group or a    halo-lower alkoxy group; a heterocyclyl group optionally substituted    by a halogen atom, a cyano group, a lower alkyl group, a halo-lower    alkyl group, a lower alkoxy group or a halo-lower alkoxy group; a    lower alkylene group,-   (3) Ring A is an unsaturated monocyclic heterocyclic ring which may    optionally be substituted by 1-3 substituents, independently    selected from the group consisting of a halogen atom, a lower alkyl    group optionally substituted by a halogen atom or a lower alkoxy    group, a lower alkoxy group optionally substituted by a halogen atom    or a lower alkoxy group, a cycloalkyl group, a cycloalkoxy group,    and an oxo group,    Ring B is an unsaturated monocyclic heterocyclic ring or an    unsaturated fused heterobicyclic ring, each of which may optionally    be substituted by 1-3 substituents, independently selected from the    group consisting of a halogen atom; a lower alkyl group optionally    substituted by a halogen atom, a lower alkoxy group or a phenyl    group; a lower alkoxy group optionally substituted by a halogen atom    or a lower alkoxy group; a cycloalkyl group; a cycloalkoxy group; a    phenyl group optionally substituted by a halogen atom, a cyano    group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy    group or a halo-lower alkoxy group; a heterocyclyl group optionally    substituted by a halogen atom, a cyano group, a lower alkyl group, a    halo-lower alkyl group, a lower alkoxy group or a halo-lower alkoxy    group; and an oxo group;-   (4) Ring A is an unsaturated fused heterobicyclic ring which may    optionally be substituted by 1-3 substituents, independently    selected from the group consisting of a halogen atom, a lower alkyl    group optionally substituted by a lower alkoxy group, a lower alkoxy    group optionally substituted by a halogen atom or a lower alkoxy    group, a cycloalkyl group, a cycloalkoxy group, and an oxo group,    Ring B is a benzene ring which may optionally be substituted by 1-3    substituents, independently selected from the group consisting of a    halogen atom; a lower alkyl group optionally substituted by a    halogen atom, a lower alkoxy group or a phenyl group; a lower alkoxy    group optionally substituted by a halogen atom or a lower alkoxy    group; a cycloalkyl group; a cycloalkoxy group; a phenyl group    optionally substituted by a halogen atom, a cyano group, a lower    alkyl group, a halo-lower alkyl group, a lower alkoxy group or a    halo-lower alkoxy group; a heterocyclyl group optionally substituted    by a halogen atom, a cyano group, a lower alkyl group, a halo-lower    alkyl group, a lower alkoxy group or a halo-lower alkoxy group; and    a lower alkylene group, or-   (5) Ring A is an unsaturated monocyclic heterocyclic ring which may    optionally be substituted by 1-3 substituents, independently    selected from the group consisting of a halogen atom, a lower alkyl    group optionally substituted by a lower alkoxy group, a lower alkoxy    group optionally substituted by a halogen atom or a lower alkoxy    group, a cycloalkyl group, a cycloalkoxy group, and an oxo group,    Ring B is an unsaturated monocyclic heterocyclic ring or an    unsaturated fused heterobicyclic ring, each of which may optionally    be substituted by 1-3 substituents, independently selected from the    group consisting of a halogen atom; a lower alkyl group optionally    substituted by a halogen atom, a lower alkoxy group or a phenyl    group; a lower alkoxy group optionally substituted by a halogen atom    or a lower alkoxy group; a cycloalkyl group; a cycloalkoxy group; a    phenyl group optionally substituted by a halogen atom, a cyano    group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy    group or a halo-lower alkoxy group; a heterocyclyl group optionally    substituted by a halogen atom, a cyano group, a lower alkyl group, a    halo-lower alkyl group, a lower alkoxy group or a halo-lower alkoxy    group; and an oxo group.

In another preferable embodiment of the present invention, Y is linkedat the 3-position of Ring A, with respect to X being the 1-position,Ring A is a benzene ring which may optionally be substituted by ahalogen atom, a lower alkyl group optionally substituted by a halogenatom, a lower alkoxy group, or a phenyl group, and Ring B is anunsaturated monocyclic heterocyclic ring or an unsaturated fusedheterobicyclic ring which may optionally be substituted by 1-3substituents, independently selected from the group consisting of ahalogen atom; a lower alkyl group optionally substituted by a halogenatom or a phenyl group; a lower alkoxy group; a phenyl group optionallysubstituted by a halogen atom, a cyano group, a lower alkyl group, ahalo-lower alkyl group, or a lower alkoxy group; a heterocyclyl groupoptionally substituted by a halogen atom, a cyano group, a lower alkylgroup, a halo-lower alkyl group, or a lower alkoxy group; and an oxogroup.

In another more preferable embodiment of the present invention, Y islinked at the 3-position of Ring A, with respect to X being the1-position, Ring A is an unsaturated monocyclic heterocyclic ring whichmay optionally be substituted by a substituent selected from a halogenatom, a lower alkyl group, and an oxo group, and Ring B is a benzenering which may optionally be substituted by a substituent selected fromthe group consisting of a halogen atom; a lower alkyl group optionallysubstituted by a halogen atom or a phenyl group; a lower alkoxy group; aphenyl group optionally substituted by a halogen atom, a cyano group, alower alkyl group, a halo-lower alkyl group, or a lower alkoxy group; aheterocyclyl group optionally substituted by a halogen atom, a cyanogroup, a lower alkyl group, a halo-lower alkyl group, or a lower alkoxygroup; and a lower alkylene group.

Preferable examples of unsaturated monocyclic heterocyclic ring includea 5- or 6-membered unsaturated heterocyclic ring containing 1 or 2hetero atoms independently selected from a nitrogen atom, an oxygenatom, and a sulfur atom. More specifically, preferred are furan,thiophene, oxazole, isoxazole, triazole, tetrazole, pyrazole, pyridine,pyrimidine, pyrazine, dihydroisoxazole, dihydropyridine, and thiazole.Preferable unsaturated fused heterobicyclic ring includes a 9- or10-membered unsaturated fused heterocyclic ring containing 1 to 4 heteroatoms independently selected from a nitrogen atom, an oxygen atom, and asulfur atom. More specifically, preferred are indoline, isoindoline,benzothiazole, benzoxazole, indole, indazole, quinoline, isoquinoline,benzothiophene, benzofuran, thienothiophene, and dihydroisoquinoline.

In a more preferred embodiment of the present invention, Ring A is abenzene ring which may optionally be substituted by a substituentselected from the group consisting of a halogen atom, a lower alkylgroup, a halo-lower alkyl group, a lower alkoxy group, and a phenylgroup, and Ring B is a heterocyclic ring selected from the groupconsisting of thiophene, furan, benzofuran, benzothiophene, andbenzothiazole, wherein the heterocyclic ring may optionally besubstituted by a substituent selected from the following group: ahalogen atom, a cyano group, a lower alkyl group, a halo-lower alkylgroup, a phenyl-lower alkyl group, a lower alkoxy group, a halo-loweralkoxy group, a phenyl group, a halophenyl group, a lower alkylphenylgroup, a lower alkoxyphenyl group, a thienyl group, a halothienyl group,a pyridyl group, a halopyridyl group, and a thiazolyl group.

In yet another preferred embodiment, Y is —CH₂—, Ring A is anunsaturated monocyclic heterocyclic ring or an unsaturated fusedheterobicyclic ring selected from the group consisting of thiophene,dihydroisoquinoline, dihydroisoxazole, triazole, pyrazole,dihydropyridine, dihydroindole, indole, indazole, pyridine, pyrimidine,pyrazine, quinoline, and a isoindoline, wherein the heterocyclic ringmay optionally substituted by a substituent selected from the followinggroup: a halogen atom, a lower alkyl group, and an oxo group, and Ring Bis a benzene ring which may optionally be substituted by a substituentselected from the following group: a halogen atom, a lower alkyl group,a halo-lower alkyl group, a lower alkoxy group, and a halo-lower alkoxygroup.

In a further preferred embodiment of the present invention, Ring A is abenzene ring which is substituted by a halogen atom or a lower alkylgroup, and Ring B is thienyl group which is substituted by phenyl groupor a heterocyclyl group in which said phenyl group and heterocyclylgroup is substituted by 1-3 substituents selected from a halogen atom, acyano group, a lower alkyl group, a halo-lower alkyl group, a loweralkoxy group, and a halo-lower alkoxy group.

Further, in another aspect of the present invention, preferable examplesof the compound of the formula I include a compound wherein Ring A is

wherein R^(1a), R^(2a), R^(3a), R^(1b), R^(2b), and R^(3b) are eachindependently a hydrogen atom, a halogen atom, a hydroxy group, analkoxy group, an alkyl group, a haloalkyl group, a haloalkoxy group, ahydroxyalkyl group, an alkoxyalkyl group, an alkoxyalkoxy group, analkenyl group, an alkynyl group, a cycloalkyl group, acycloalkylidenemethyl group, a cycloalkenyl group, a cycloalkyloxygroup, a phenyl group, a phenylalkoxy group, a cyano group, a nitrogroup, an amino group, a mono- or di-alkylamino group, an alkanoylaminogroup, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, amono- or di-alkylcarbamoyl group, an alkanoyl group, analkylsulfonylamino group, a phenylsulfonylamino group, an alkylsulfinylgroup, an alkylsulfonyl group, or a phenylsulfonyl group, andRing B is

wherein R^(4a) and R^(5a) are each independently a hydrogen atom; ahalogen atom; a hydroxy group; an alkoxy group; an alkyl group; ahaloalkyl group; a haloalkoxy group; a hydroxyalkyl group; analkoxyalkyl group; a phenylalkyl group; an alkoxyalkoxy group; ahydroxyalkoxy group; an alkenyl group; an alkynyl group; a cycloalkylgroup; a cycloalkylidenemethyl group; a cycloalkenyl group; acycloalkyloxy group; a phenyloxy group; a phenylalkoxy group; a cyanogroup; a nitro group; an amino group; a mono- or di-alkylamino group; analkanoylamino group; a carboxyl group; an alkoxycarbonyl group; acarbamoyl group; a mono- or di-alkylcarbamoyl group; an alkanoyl group;an alkylsulfonylamino group; a phenylsulfonylamino group; analkylsulfinyl group; an alkylsulfonyl group; a phenylsulfonyl group; aphenyl group optionally substituted by a halogen atom, a cyano group, analkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, analkylenedioxy group, an alkyleneoxy group, a mono- or di-alkylaminogroup, a carbamoyl group, or a mono- or di-alkylcarbamoyl group; or aheterocyclyl group optionally substituted by a halogen atom, a cyanogroup, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxygroup, a carbamoyl group, or a mono- or di-alkylcarbamoyl group, orR^(4a) and R^(5a) are bonded to each other at the terminals thereof toform an alkylene group; andR^(4b), R^(5b), R^(4c) and R^(5c) are each independently a hydrogenatom; a halogen atom; a hydroxy group; an alkoxy group; an alkyl group;a haloalkyl group; a haloalkoxy group; a hydroxyalkyl group; analkoxyalkyl group; a phenylalkyl group; an alkoxyalkoxy group; ahydroxyalkoxy group; an alkenyl group; an alkynyl group; a cycloalkylgroup; a cycloalkylidenemethyl group; a cycloalkenyl group; acycloalkyloxy group; a phenyloxy group; a phenylalkoxy group; a cyanogroup; a nitro group; an amino group; a mono- or di-alkylamino group; analkanoylamino group; a carboxyl group; an alkoxycarbonyl group; acarbamoyl group; a mono- or di-alkylcarbamoyl group; an alkanoyl group;an alkylsulfonylamino group; a phenylsulfonylamino group; analkylsulfinyl group; an alkylsulfonyl group; a phenylsulfonyl group; aphenyl group optionally substituted by a halogen atom, a cyano group, analkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, amethylenedioxy group, an ethyleneoxy group, or a mono- or di-alkylaminogroup; or a heterocyclyl group optionally substituted by a halogen atom,a cyano group, an alkyl group, a haloalkyl group, an alkoxy group or ahaloalkoxy group.

More preferred is a compound wherein R^(1a), R^(2a), R^(3a), R^(1b),R^(2b), and R^(3b) are each independently a hydrogen atom, a halogenatom, a lower alkyl group, a halo-lower alkyl group, a lower alkoxygroup, or a phenyl group;

R^(4a) and R^(5a) are each independently a hydrogen atom; a halogenatom; a lower alkyl group; a halo-lower alkyl group; a phenyl-loweralkyl group; a phenyl group optionally substituted by a halogen atom, acyano group, a lower alkyl group, a halo-lower alkyl group, a loweralkoxy group, a halo-lower alkoxy group, a methylenedioxy group, anethyleneoxy group, a mono- or di-lower alkylamino group, a carbamoylgroup, or a mono- or di-lower alkylcarbamoyl group; or a heterocyclylgroup optionally substituted by a halogen atom, a cyano group, a loweralkyl group, a lower alkoxy group, a carbamoyl group, or a mono- ordi-lower alkylcarbamoyl group, or R^(4a) and R^(5a) are bonded to eachother at the terminals thereof to form a lower alkylene group; andR^(4b), R^(5b), R^(4c) and R^(5c) are each independently a hydrogenatom, a halogen atom, a lower alkyl group, a halo-lower alkyl group, alower alkoxy group, or a halo-lower alkoxy group.

Further preferred is a compound in which Ring B is

wherein R^(4a) is a phenyl group optionally substituted by a halogenatom, a cyano group, a lower alkyl group, a halo-lower alkyl group, alower alkoxy group, a halo-lower alkoxy group, a methylenedioxy group,an ethyleneoxy group, a mono- or di-lower alkylamino group, a carbamoylgroup, or a mono- or di-lower alkylcarbamoyl group; or a heterocyclylgroup optionally substituted by a halogen atom, a cyano group, a loweralkyl group, a lower alkoxy group, a carbamoyl group, or a mono- ordi-lower alkylcarbamoyl group, andR^(5a) is a hydrogen atom, orR^(4a) and R^(5a) are bonded to each other at the terminals thereof toform a lower alkylene group.

Further more preferred is a compound in which Ring A is

wherein R^(1a) is a halogen atom, a lower alkyl group, or a lower alkoxygroup, and R^(2a) and R^(3a) are hydrogen atoms; and Ring B is

wherein R^(4a) is a phenyl group optionally substituted by a substituentselected from the group consisting of a halogen atom, a cyano group, alower alkyl group, a halo-lower alkyl group, a lower alkoxy group, ahalo-lower alkoxy group, a mono- or di-lower alkylamino group, acarbamoyl group, and a mono- or di-lower alkylcarbamoyl group; or aheterocyclyl group optionally substituted by a halogen atom, a cyanogroup, a lower alkyl group, a lower alkoxy group, a carbamoyl group, ora mono- or di-lower alkylcarbamoyl group, and R^(5a) is a hydrogen atom,and Y is —CH₂—.

In more preferable embodiment, R^(4a) is a phenyl group optionallysubstituted by a halogen atom, a cyano group, a lower alkyl group, ahalo-lower alkyl group, a lower alkoxy group, or a halo-lower alkoxygroup; or a heterocyclyl group optionally substituted by a halogen atom,a cyano group, a lower alkyl group, or a lower alkoxy group.

In another preferable embodiment of the present invention, a preferablecompound can be represented by the following formula IA:

wherein R^(A) is a halogen atom, a lower alkyl group or a lower alkoxygroup; R^(B) is a phenyl group optionally substituted by 1-3substituents selected from a halogen atom, a cyano group, a lower alkylgroup, a halo-lower alkyl group, a lower alkoxy group, a halo-loweralkoxy group, a methylenedioxy group, an ethyleneoxy group, a mono- ordi-lower alkylamino group, a carbamoyl group, and a mono- or di-loweralkylcarbamoyl group; or a heterocyclyl group optionally substituted by1-3 substituents selected from a halogen atom, a cyano group, a loweralkyl group, a halo-lower alkyl group, a lower alkoxy group, ahalo-lower alkoxy group, amono- or di-lower alkylamino group, acarbamoyl group, and a mono- or di-lower alkylcarbamoyl group; and R^(c)is hydrogen atom; or R^(B) and R^(c) taken together are a fused benzenering which may be substituted by a halogen atom, a lower alkyl group, ahalo-lower alkyl group, a lower alkoxy group or a halo-lower alkoxygroup.

In a preferable embodiment, R^(A) is a halogen atom or a lower alkylgroup, R^(c) is hydrogen atom, and R^(B) is phenyl group substituted by1-3 substituents selected from a halogen atom, a cyano group, a loweralkyl group, a halo-lower alkyl group, a lower alkoxy group, ahalo-lower alkoxy group, a methylenedioxy group, an ethyleneoxy group, amono- or di-lower alkylamino group, a carbamoyl group, and a mono- ordi-lower alkylcarbamoyl group; or a heterocyclyl group substituted by1-3 substituents selected from the group consisting of a halogen atom, acyano group, a lower alkyl group, a halo-lower alkyl group, a loweralkoxy group, a halo-lower alkoxy group, a mono- or di-lower alkylaminogroup, a carbamoyl group, and a mono- or di-lower alkylcarbamoyl group.The chemical structure of such compounds are represented by thefollowing formula (IA′)

wherein R^(A) is a halogen atom, or a lower alkyl group, Ring C is aphenyl group substituted by 1-3 substituents selected from the groupconsisting of a halogen atom, a cyano group, a lower alkyl group, ahalo-lower alkyl group, a lower alkoxy group, a halo-lower alkoxy group,a methylenedioxy group, an ethyleneoxy group, a mono- or di-loweralkylamino group, a carbamoyl group, and a mono- or di-loweralkylcarbamoyl group; or a heterocyclyl group substituted by 1-3substituents selected from the group consisting of a halogen atom, acyano group, a lower alkyl group, a halo-lower alkyl group, a loweralkoxy group, a halo-lower alkoxy group, a mono- or di-lower alkylaminogroup, a carbamoyl group, and a mono- or di-lower alkylcarbamoyl group.

In a more preferable embodiment, Ring C is a phenyl group substituted by1-3 substituents selected from the group consisting of a halogen atom, acyano group, a lower alkyl group, a halo-lower alkyl group, a loweralkoxy group, a halo-lower alkoxy group, and a mono- or di-loweralkylamino group; or a heterocyclyl group substituted by a substituentselected from the group consisting of a halogen atom, a cyano group, alower alkyl group, a halo-lower alkyl group, a lower alkoxy group, and ahalo-lower alkoxy group.

Among them, a compound in which Ring C is a phenyl group substituted bya halogen atom, a cyano group, a lower alkyl group, a halo-lower alkylgroup, a lower alkoxy group or a halo-lower alkoxy group; or aheterocyclyl group substituted by a halogen atom, a cyano group, a loweralkyl group, or a lower alkoxy group is preferred.

A preferred heterocyclyl group includes a 5- or 6-membered heterocyclylgroup containing 1 or 2 hetero atoms independently selected from thegroup consisting of a nitrogen atom, an oxygen atom, and a sulfur atom,or a 9- or 10-membered heterocyclyl group containing 1 to 4 hetero atomsindependently selected from the group consisting of a nitrogen atom, anoxygen atom, and a sulfur atom. Specifically, a thienyl group, a pyridylgroup, a pyrimidyl group, a pyrazinyl group, pyrazolyl group, athiazolyl group, a quinolyl group, a tetrazolyl group and an oxazolylgroup are preferred.

In a further preferable embodiment, Ring C is a phenyl group substitutedby a halogen atom or a cyano group, or a pyridyl group substituted by ahalogen atom.

In another preferable embodiment of the present invention, preferred isa compound in which Ring A is

wherein R^(1a) is a halogen atom, a lower alkyl group, or a lower alkoxygroup, and R^(2a) and R^(3a) are hydrogen atoms; and Ring B is

wherein R^(4b) and R^(5b) are each independently a hydrogen atom, ahalogen atom, a lower alkyl group, a halo-lower alkyl group, a loweralkoxy group, or a halo-lower alkoxy group.

In another aspect of the present invention, preferable examples of thecompound I include a compound represented by the following formula IB:

wherein R⁸, R⁹ and R¹⁰ are each independently a hydrogen atom, a halogenatom, a hydroxy group, an alkoxy group, an alkyl group, a haloalkylgroup, a haloalkoxy group, a hydroxyalkyl group, an alkoxyalkyl group,an alkoxyalkoxy group, an alkenyl group, an alkynyl group, a cycloalkylgroup, a cycloalkylidenemethyl group, a cycloalkenyl group, acycloalkyloxy group, an aryloxy group, an arylalkoxy group, a cyanogroup, a nitro group, an amino group, a mono- or di-alkylamino group, analkylcarbonylamino group, a carboxyl group, an alkoxycarbonyl group, acarbamoyl group, a mono- or di-alkylcarbamoyl group, an alkanoyl group,an alkylsulfonylamino group, an arylsulfonylamino group, analkylsulfinyl group, an alkylsulfonyl group, or an arylsulfonyl group;and a group represented by:

wherein R^(6a) and R^(7a) are each independently a hydrogen atom, ahalogen atom, a hydroxy group, an alkoxy group, an alkyl group, ahaloalkyl group, a haloalkoxy group, a hydroxyalkyl group, analkoxyalkyl group, an alkoxyalkoxy group, an alkenyl group, an alkynylgroup, a cycloalkyl group, a cycloalkylidenemethyl group, a cycloalkenylgroup, a cycloalkyloxy group, an aryloxy group, an arylalkoxy group, acyano group, a nitro group, an amino group, a mono- or di-alkylaminogroup, an alkylcarbonylamino group, a carboxyl group, an alkoxycarbonylgroup, a carbamoyl group, a mono- or di-alkylcarbamoyl group, analkanoyl group, an alkylsulfonylamino group, an arylsulfonylamino group,an alkylsulfinyl group, an alkylsulfonyl group, or an arylsulfonyl groupand R^(6b) and R^(7b) are each independently a hydrogen atom, a halogenatom, an alkyl group, a haloalkyl group, or an alkoxy group.

Among the compounds represented by the formula IB, more preferred is acompound in which R⁸, R⁹ and R¹⁰ are each independently a hydrogen atom,a halogen atom, a lower alkyl group, a cycloalkyl group, a hydroxy-loweralkyl group, a halo-lower alkyl group, a lower alkoxy-lower alkyl group,a lower alkoxy group, a cycloalkoxy group, a halo-lower alkoxy group, ora lower alkoxy-lower alkoxy group, and a group represented by:

wherein R^(a), R^(7a) are each independently a hydrogen atom, a halogenatom, a lower alkyl group, a cycloalkyl group, a hydroxy-lower alkylgroup, a halo-lower alkyl group, a lower alkoxy-lower alkyl group, alower alkoxy group, a cycloalkoxy group, a halo-lower alkoxy group, or alower alkoxy-lower alkoxy group, or a group represented by:

wherein R^(6b) and R^(7b) are each independently a hydrogen atom, ahalogen atom, a lower alkyl group, a halo-lower alkyl group, or a loweralkoxy group.

In another aspect of the present invention, preferable examples of thecompound I include a compound represented by the following formula IC:

wherein Ring B′ is an optionally substituted benzene ring, an optionallysubstituted unsaturated monocyclic heterocyclic ring, or an optionallysubstituted unsaturated fused heterobicyclic ring.

Preferable examples of Ring B′ include a benzene ring and a heterocyclicring, both of which may have a substituent (s) selected from the groupconsisting of a halogen atom; a cyano group; a lower alkyl groupoptionally substituted by a halogen atom; a lower alkoxy groupoptionally substituted by a halogen atom; a lower alkanoyl group; amono- or di-lower alkylamino group; a lower alkoxycarbonyl group; acarbamoyl group; a mono- or di-lower alkylcarbamoyl group; a phenylgroup optionally substituted by a substituent(s) selected from a halogenatom, a cyano group, a lower alkyl group optionally substituted by ahalogen atom, a lower alkoxy group optionally substituted by a halogenatom, a lower alkanoyl group, a mono- or di-lower alkylamino group, alower alkoxycarbonyl group, a carbamoyl group, or a mono- or di-loweralkylcarbamoyl group; a heterocyclyl group optionally substituted by asubstituent (s) selected from a halogen atom, a cyano group, a loweralkyl group optionally substituted by a halogen atom, a lower alkoxygroup optionally substituted by a halogen atom, a lower alkanoyl group,a mono- or di-lower alkylamino group, a lower alkoxycarbonyl group, acarbamoyl group, or a mono- or di-lower alkylcarbamoyl group; analkylene group; and an oxo group.

More preferable examples of Ring B′ include a benzene ring which may besubstituted by a substituent selected from the group consisting of ahalogen atom; a cyano group; a lower alkyl group optionally substitutedby a halogen atom; a lower alkoxy group optionally substituted by ahalogen atom; a mono- or di-lower alkylamino group; a phenyl groupoptionally substituted by a halogen atom, a cyano group, a lower alkylgroup optionally substituted by a halogen atom, a lower alkoxy groupoptionally substituted by a halogen atom; a heterocyclyl groupoptionally substituted by a halogen atom, a cyano group, a lower alkylgroup optionally substituted by a halogen atom, a lower alkoxy groupoptionally substituted by a halogen atom.

Preferred compound of the present invention may be selected from thefollowing group:

-   1-(β-D-glucopyranosyl)-4-chloro-3-(6-ethylbenzo[b]thiophen-2-ylmethyl)benzene;-   1-(β-D-glucopyranosyl)-4-chloro-3-[5-(5-thiazolyl)-2-thienylmethyl]benzene;-   1-(β-D-glucopyranosyl)-4-chloro-3-(5-phenyl-2-thienyl-methyl)benzene;-   1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene;-   1-(β-D-glucopyranosyl)-4-chloro-3-[5-(2-pyrimidinyl)-2-thienylmethyl]benzene;-   1-(β-D-glucopyranosyl)-4-methyl-3-[5-(2-pyrimidinyl)-2-thienylmethyl]benzene;-   1-(β-D-glucopyranosyl)-4-chloro-3-[5-(3-cyanophenyl)-2-thienylmethyl]benzene;-   1-(β-D-glucopyranosyl)-4-chloro-3-[5-(4-cyanophenyl)-2-thienylmethyl]benzene;-   1-(β-D-glucopyranosyl)-4-methyl-3-[5-(6-fluoro-2-pyridyl)-2-thienylmethyl]benzene;-   1-(β-D-glucopyranosyl)-4-chloro-3-[5-(6-fluoro-2-pyridyl)-2-thienylmethyl]benzene;-   1-(β-D-glucopyranosyl)-4-methyl-3-[5-(3-difluoromethyl-phenyl)-2-thienylmethyl]benzene;-   1-(β-D-glucopyranosyl)-4-methyl-3-[5-(3-cyanophenyl)-2-thienylmethyl]benzene;-   1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-cyanophenyl)-2-thienylmethyl]benzene;-   1-(β-D-glucopyranosyl)-4-chloro-3-[5-(6-fluoro-3-pyridyl)-2-thienylmethyl]benzene;-   1-(β-D-glucopyranosyl)-4-fluoro-3-(5-(3-cyanophenyl)-2-thienylmethyl)benzene;    the pharmaceutically acceptable salt thereof; and    the prodrug thereof.

Particularly Preferred compounds of the present invention include:

1-(β-D-glucopyranosyl)-4-methyl-3-[5-(3-cyano-phenyl)-2-thienylmethyl]benzene,or a pharmaceutically acceptable salt thereof, or a prodrug thereof;

1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-cyano-phenyl)-2-thienylmethyl]benzene,or a pharmaceutically acceptable salt thereof, or a prodrug thereof;

1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluoro-phenyl)-2-thienylmethyl]benzene,or a pharmaceutically acceptable salt thereof, or a prodrug thereof;

1-(β-D-glucopyranosyl)-4-chloro-3-[5-(3-cyano-phenyl)-2-thienylmethyl]benzene,or a pharmaceutically acceptable salt thereof, or a prodrug thereof;

1-(β-D-glucopyranosyl)-4-methyl-3-[5-(6-fluoro-2-pyridyl)-2-thienylmethyl]benzene,or a pharmaceutically acceptable salt thereof, or a prodrug thereof;

1-(β-D-glucopyranosyl)-4-chloro-3-[5-(6-fluoro-2-pyridyl)-2-thienylmethyl]benzene,or a pharmaceutically acceptable salt thereof, or a prodrug thereof;

1-(β-D-glucopyranosyl)-4-chloro-3-[5-(6-fluoro-3-pyridyl)-2-thienylmethyl]benzene,or a pharmaceutically acceptable salt thereof, or a prodrug thereof; and

1-(β-D-glucopyranosyl)-4-fluoro-3-(5-(3-cyano-phenyl)-2-thienylmethyl)benzene,or a pharmaceutically acceptable salt thereof, or a prodrug thereof.

The compound (I) of the present invention exhibits an excellentinhibitory activity against sodium-dependent glucose transporter, and anexcellent blood glucose lowering effect. Therefore, the compound of thepresent invention is usefule for treating or delaying the progression oronset of diabetes mellitus, diabetic retinopathy, diabetic neuropathy,diabetic nephropathy, delayed wound healing, insulin resistance,hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids,elevated blood levels of glycerol, hyperlipidemia, obesity,hypertriglyceridemia, Syndrome X, diabetic complications,atherosclerosis, or hypertension. In particuler, the compound of thepresent invention is useful in the treatment or the prophylaxis ofdiabetes mellitus (type 1 and type 2 diabetes mellitus, etc.), diabeticcomplications (such as diabetic retinopathy, diabetic neuropathy,diabetic nephropathy) or obesity, or is useful in the treatment ofpostprandial hyperglycemia.

The compound (I) of the present invention or a pharmaceuticallyacceptable salt thereof may be administered either orally orparenterally, and can be used in the form of a suitable pharmaceuticalpreparation. Suitable pharmaceutical preparation for oral administrationincludes, for example, solid preparation such as tablets, granules,capsules, powders, etc., or solution preparations, suspensionpreparations, or emulsion preparations, etc. Suitable pharmaceuticalpreparation for parenteral administration includes, for example,suppositories; injection preparations and intravenous drip preparationsusing distilled water for injection, physiological saline solution oraqueous glucose solution; or inhalant preparations.

The dosage of the present compound (I) or a pharmaceutically acceptablesalt thereof may vary according to the administration routes, ages, bodyweight, conditions of a patient, or kinds and severity of a disease tobe treated, and it is usually in the range of about 0.1 to 50 mg/kg/day,preferably in the range of about 0.1 to 30 mg/kg/day.

The compound of the formula I may be used, if necessary, in combinationwith one or more of other antidiabetic agents, one or more agents fortreating diabetic complications, and/or one or more agents for treatmentof other diseases. The present compound and these other agents may beadministered in the same dosage form, or in a separate oral dosage formor by injection.

The other antidiabetic agents include, for example, antidiabetic orantihyperglycemic agents including insulin, insulin secretagogues, orinsulin sensitizers, or other antidiabetic agents having an actionmechanism different from SGLT inhibition, and 1, 2, 3 or 4 of theseother antidiabetic agents may preferably be used. Concrete examplesthereof are biguanide compounds, sulfonylurea compounds, α-glucosidaseinhibitors, PPARγ agonists (e.g., thiazolidinedione compounds), PPARα/γdual agonists, dipeptidyl peptidase IV (DPP4) inhibitors, mitiglinidecompounds, and/or nateglinide compounds, and insulin, glucagon-likepeptide-1 (GLP-1), PTP1B inhibitors, glycogen phosphorylase inhibitors,RXR modulators, and/or glucose 6-phosphatase inhibitors.

The agents for treatment of other diseases include, for example, ananti-obesity agent, an antihypertensive agent, an antiplatelet agent, ananti-atherosclerotic agent and/or a hypolipidemic agent.

The SGLT inhibitors of the formula I may be used in combination withagents for treatment of diabetic complications, if necessary. Theseagents include, for example, PKC inhibitors and/or ACE inhibitors.

The dosage of those agents may vary according to ages, body weight, andconditions of patients, and administration routes, dosage forms, etc.

These pharmaceutical compositions may be orally administered tomammalian species including human beings, apes, dogs, etc., for example,in the dosage form of tablet, capsule, granule or powder, orparenterally administered in the form of injection preparation, orintranasally, or in the form of transdermal patch.

The present compound of the formula I may be prepared by the followingProcesses.

Process 1

The compound of the formula I may be prepared by a method as shown inthe following scheme:

wherein R^(11a) is a hydrogen atom or a protecting group for a hydroxygroup, and R^(11a), R^(11c) and R^(11d) are each independently aprotecting group for a hydroxy group, and other symbols are as definedabove.

The compound of the formula I may be prepared by deprotecting thecompound of the formula II.

In the compound of the formula II, the protecting group for hydroxygroup may be any conventional protecting groups, and a benzyl group, anacetyl group, and an alkylsily group such as a trimethylsilyl group maybe used. Further, the protecting group for hydroxy group may form acetalor silylacetal together with adjacent hydroxy groups. Examples of suchprotecting group include an alkylidene group such as an isopropylidenegroup, a sec-butylidene group, etc., a benzylidene group, or adialkylsilylene group such as di-tert-butylsilylene group, etc., whichcan be formed, for example, by combining R^(11c) and R^(11d) at theterminal thereof.

The deprotection can be carried out according to the kinds of protectinggroup to be removed, for example, by conventional processes such asreduction, hydrolysis, acid treatment, fluoride treatment, etc.

For example, when a benzyl group is to be removed, the deprotection canbe carried out by (1) catalytic reduction using a palladium catalyst(e.g., palladium-carbon, palladium hydroxide) under hydrogen atmospherein a suitable solvent (e.g., methanol, ethanol, ethyl acetate); (2)treatment with an dealkylating agent such as boron tribromide, borontrichloride, boron trichloride dimethylsulfide complex, oriodotrimethylsilane in a suitable solvent (e.g., dichloromethane); or(3) treatment with a lower alkylthiol such as ethanethiol in thepresence of a Lewis acid (e.g., boron trifluoride.diethyl ether complex)in a suitable solvent (e.g., dichloromethane).

When a protecting group is removed by hydrolysis, the hydrolysis can becarried out by treating the compound of formula II with a base (e.g.,sodium hydroxide, potassium hydroxide, lithium hydroxide, sodiummethoxide, sodium ethoxide, etc.) in a suitable solvent (e.g.,tetrahydrofuran, dioxane, methanol, ethanol, water, etc.).

Acid treatment can be carried out by treating the compound of formula IIwith an acid (e.g., hydrochloric acid, p-toluenesulfonic acid,methanesulfonic acid, trifluoroacetic acid, etc.) in a suitable solvent(e.g., methanol, ethanol, etc.).

In case of the fluoride treatment, it can be carried out by treating thecompound of formula II with a fluoride (e.g., hydrogen fluoride,hydrogen fluoride-pyridine, tetrabutylammonium fluoride, etc.) in asuitable solvent (e.g., acetic acid, a lower alcohol (methanol, ethanol,etc.), acetonitrile, tetrahydrofuran, etc.).

The deprotection reaction can be preferably carried out under cooling orwith heating, for example, at a temperature of from 0° C. to 50° C.,more preferably at a temperature of from 0° C. to room temperature.

Accordingly, a compound of formula (IA′):

wherein the symbols are the same as defined above, can be prepared bydeprotecting a compound of formula (II-A):

wherein the symbols are the same as defined above, as described above.Process 2

The compound of the formula I wherein X is a carbon atom may be preparedby a method as shown in the following scheme:

wherein R¹² is a lower alkyl group, and other symbols are as definedabove.

The compound of the formula I-a may be prepared by reducing the compoundof the formula III.

The reduction can be carried out by treatment with a silane reagent, inthe presence of an acid, in a suitable solvent or in the absence of asolvent.

As the acid, for example, a Lewis acid such as boron trifluoride.diethylether complex, titanium tetrachloride, etc., and a strong organic acidsuch as trifluoroacetic acid, methanesulfonic acid, etc., may preferablybe used.

As the silane reagent, for example, a trialkylsilane such astriethylsilane, triisopropylsilane, etc. may preferably be used.

As the solvent, any kinds of solvent may be used as long as it does notaffect the reaction, and for example, acetonitrile, dichloromethane, oran acetonitrile/dichloromethane mixture may preferably be used.

Accordingly, the compound of the formula (IA′):

wherein the symbols are the same as defined above, can be prepared byreducing a compound of formula (III-A):

wherein the symbols are the same as defined above, as described above.Process 3

The compound of the formula I wherein X is a carbon atom may be preparedby a method as shown in the following scheme:

wherein the symbols are as defined above.

Namely, the compound of the formula I-b may be prepared by reducing thecompound of the formula IV.

The reduction can be carried out in a manner similar to Process 2. Inother words, it can be carried out by treatment with a silane reagent(e.g., triethylsilane, etc.), in the presence of a Lewis acid (e.g.,boron trifluoride.diethyl ether complex, etc.), in a suitable solvent(e.g., acetonitrile, dichloromethane, etc.).

The compound of the present invention thus obtained may be isolated andpurified by a conventional method well known in the organic syntheticchemistry such as recrystallization, column chromatography, etc.

The starting compound represented by the formula (II), (III) or (IV) maybe prepared by either one of the following steps (a)-(l).

Steps (a) and (b):

In the above scheme, R¹³ is (1) a bromine atom or an iodine atom when Xis a carbon atom; or (2) a hydrogen atom when X is a nitrogen atom,R^(11e) is a protecting group for hydroxy group, and the other symbolsare as defined above.Step (a)

Among the compounds of the formula II, the compound wherein X is acarbon atom may be prepared by coupling the compound of the formula VIIwith the compound of the formula VI to give the compound of formula V,followed by reduction of the compound of the formula V.

The coupling reaction can be carried out by lithiating the compound ofthe formula VII, followed by reacting the resultant with the compound ofthe formula VI.

In particular, the compound of the formula VII can be treated with analkyllithium, followed by reacting the resultant with the compound ofthe formula VI. As the alkyllithium, methyl lithium, n-butyl lithium,t-butyl lithium, etc. are preferably used. The solvent may be anysolvent which does not disturb the reaction, and ethers such astetrahydrofuran, diethyl ether, etc., are preferably used. This reactioncan be carried out from under cooling (e.g., at −78° C.) to roomtemperature.

The reduction can be carried out in a manner similar to Process 2.Namely, it can be carried out by treating the compound of formula V witha silane reagent (e.g., triethylsilane, etc.) in the presence of a Lewisacid (e.g., boron trifluoride.diethyl ether complex, etc.) in a suitablesolvent (e.g., acetonitrile, dichloromethane, etc.).

Step (b)

Among the compounds of the formula II, the compound wherein X is anitrogen atom may be prepared by silylating the compound of the formulaVII in a solvent, followed by reacting the resultant with the compoundof the formula VIII (e.g., an α- or β-D-glucose pentaacetate, etc.) inthe presence of a Lewis acid.

The silylation reaction can be carried out by treating the compound offormula VII with a silylating agent in a solvent. The silylating agentincludes, for example, N,O-bis(trimethylsilyl)acetamide,1,1,1,3,3,3-hexamethyl-disilazane, etc.

The solvent may be, for example, halogenated hydrocarbons such asdichloromethane, dichloroethane, chloroform, etc., ethers such asdiethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, etc., acetonitrile,etc.

This reaction is preferably carried out under cooling or with heating,for example, at a temperature of from 0° C. to 60° C., preferably at atemperature of from room temperature to 60° C.

The reaction with the compound of the formula VIII can be carried out ina solvent in the presence of a Lewis acid.

The Lewis acid includes, for example, trimethylsilyltrifluoromethanesulfonate, titanium tetrachloride, tin tetrachloride,boron trifluoride.diethyl ether complex.

The solvent may be, for example, halogenated hydrocarbons such asdichloromethane, dichloroethane, chloroform, etc., acetonitrile, etc.

This reaction can be carried out under cooling or with heating, forexample, at a temperature of from 0° C. to 100° C., preferably at atemperature of from room temperature to 60° C.

Step (c):

Among the compounds of the formula II, the compound wherein X is acarbon atom and R^(11a) is a hydrogen atom may be prepared by a methodas shown in the following scheme:

wherein R^(13a) is a bromine atom or an iodine atom, and the othersymbols are as defined above.

Namely, the compounds of the formula II-a may be prepared by couplingthe compound of the formula VII-a with the compound of the formula X oran ester thereof to give the compound of the formula IX, followed byhydrating the compound of the formula IX.

The ester of the compound of the formula X includes, for example, alower alkyl ester thereof, and a compound represented by the formula XI:

wherein R¹⁴ is a lower alkyl group, m is 0 or 1, and the other symbolsare as defined above.

The coupling reaction of the compound of the formula VII-a with thecompound of the formula X or an ester thereof can be carried out in thepresence of a base and a palladium catalyst in a suitable solvent.

The base includes an inorganic base such as an alkali metal carbonate(e.g., sodium carbonate, potassium carbonate, etc.) an alkali metalhydrogen carbonate (e.g., sodium hydrogen carbonate, potassium hydrogencarbonate, etc.), an alkali metal hydroxide (e.g., sodium hydroxide,potassium hydroxide, etc.), potassium fluoride, potassium phosphate,etc., and an organic base such as a tri-lower alkylamine (e.g.,triethylamine, diisopropylethylamine, etc.), a cyclic tertiary amine(e.g., 1,4-diazabicyclo[2.2.2]octane,1,5-diazabicyclo[4.3.0]-nona-5-ene, 1,8-diazabicyclo[5.4.0]undeca-7-ene,etc.).

The palladium catalyst may be a conventional catalyst such astetrakis(triphenyl)phosphine palladium(0), palladium(II) acetate,palladium(II) chloride, bis(triphenyl)phosphine palladium(II) chloride,palladium(II) chloride.1,1-bis(diphenylphosphino)ferrocene complex, etc.

The solvent may be any inert solvent which does not disturb thereaction, for example, ethers such as tetrahydrofuran, dioxane,1,2-dimethoxyethane, etc., amide solvents such as N,N-dimethylformamide,1,3-dimethyl-2-imidazolidinone, etc., aromatic hydrocarbons such astoluene, xylene, etc., dimethylsulfoxide, water, and if desired, amixture of two or more of these solvents.

This reaction is preferably carried out with heating, for example, at atemperature of from 50° C. to a boiling point of the reaction mixture,and more preferably at a temperature of from 50° C. to 100° C.

The hydration reaction of the compound of the formula IX can be carriedout, for example, by hydroboration, more specifically, by reacting withdiborane, borane.tetrahydrofuran complex, or 9-borabicyclononane, etc.in a suitable solvent, followed by treating with hydrogen peroxidesolution in the presence of a base (e.g., an alkali metal hydroxide suchas sodium hydroxide, etc.), or by treating with an oxidizing reagentsuch as sodium perborate, and oxodiperoxymolybdenum (pyridine)(hexamethylphosphoric triamide) in a suitable solvent.

The solvent may be any inert solvent which does not disturb thereaction, for example, ethers such as diethyl ether, diisopropyl ether,tetrahydrofuran, dioxane, 1,2-dimethoxy-ethane, etc., aromatichydrocarbons such as benzene, toluene, xylene, etc., water, and ifdesired, a mixture of two or more of these solvents. This reaction canbe carried out at a temperature of a broad range such as under coolingor with heating, and preferably carried out at a temperature of from−10° C. to a boiling point of the reaction mixture.

Step (d):

Among the compound of the formula II, the compound wherein Ring A is abenzene ring may be prepared in a method as shown in the followingscheme:

wherein the symbols are as defined above.

Namely, the compounds of the formula II-b may be prepared by couplingthe compound of the formula XIV with the compound of the formula XIII,to give the compound of the formula XII, followed by reduction of thecompound of the formula XII.

The coupling reaction can be carried out in a manner similar to Step(a). Namely, it can be carried out by lithiating the compound of formulaXIV with an alkyl lithium (e.g., n-butyl lithium, tert-butyl lithium,etc.) in a suitable solvent (e.g., diethyl ether, tetrahydrofuran,etc.), followed by reacting the resultant with the compound (XIII).

The reduction reaction can be carried out by (1) treatment with a silanereagent (e.g., trialkyl silane such as triethyl silane, etc.) in asuitable solvent (e.g., acetonitrile, dichloromethane, etc.), at −30° C.to 60° C., in the presence of a Lewis acid such as borontrifluoride.diethyl ether complex or trifluoroacetic acid, (2) treatmentwith iodotrimethylsilane, or (3) treatment with a reducing agent (e.g.,borohydrides such as sodium boron hydride, sodium triacetoxyborohydride,etc., aluminum hydrides such as lithium aluminum hydride, etc.) in thepresence of an acid (e.g., a strong acid such as trifluoroacetic acid,etc., and a Lewis acid such as aluminum chloride, etc.).

Step (e):

The compound of the formula III may be prepared by a method as shown inthe following scheme:

wherein the symbols are as defined above.

Namely, the compound of the formula III may be prepared by deprotectingthe compound of the formula V which is a synthetic intermediate of Step(a), followed by treating the resultant compound with an acid in analcohol solvent.

The deprotection reaction can be carried out in a manner similar toProcess 1. Namely, it can be carried out by subjecting the compound V toan acid treatment, reduction, or a fluoride treatment, etc.

Following the deprotection reaction, the resultant compound is treatedwith an acid in a suitable alcohol. The acid includes, for example, aninorganic acid such as hydrochloric acid, nitric acid, sulfuric acid,etc., an organic acid such as p-toluenesulfonic acid, methanesulfonicacid, trifluoroacetic acid, etc. The alcohol includes a conventionalalkyl alcohol which does not disturb the reaction, for example,methanol, ethanol, n-propanol, i-propanol, n-butanol, etc.

Additionally, the deprotection reaction and acid treatment may becarried out in the same step, depending on the kind of the protectinggroup.

Step (f):

The compound of the formula IV may be prepared by a method as shown inthe following scheme:

wherein the symbols are as defined as above.

First, the compound of the formula XVI is coupled with the compound ofthe formula VI to give the compound of the formula XV. Then, afterprotecting groups are removed from the compound of the formula XV, theresultant is treated with an acid in an alcohol to give the compound ofthe formula IV.

The coupling reaction can be carried out in a manner similar to Step(a). Namely, the compound XVI is treated with an alkyl lithium (e.g.,n-butyl lithium, tert-butyl lithium, etc,) in a suitable solvent (e.g.,diethyl ether, tetrahydrofuran, etc.), followed by reacting theresultant with the compound VI.

The removal of protecting groups and the acid treatment are carried outin a manner similar to Step (e). Namely, it can be carried out bysubjecting the compound XV to reduction, acid treatment or fluoridetreatment, depending on the kind of the protecting group to be removed,followed by treating the resultant with an acid (e.g., hydrochloricacid, p-toluenesulfonic acid, methanesulfonic acid, trifluoroaceticacid, etc.) in a suitable solvent (e.g., methanol, ethanol, etc.).

Step (g):

The compound of the formula II may be prepared by a method as shown inthe following scheme:

wherein R²⁰ is a trialkylstannyl group, a dihydroxyboryl group or anester thereof, and the other symbols are as defined above. Examples ofesters of dihydroxyboryl group include an ester with a lower alkylalcohol such as methanol and ethanol and an ester with a lower alkylenediol such as pinacol.

Namely, the compound of the formula II may be prepared by coupling thecompound XVII with the compound XVIII in a suitable solvent, in thepresence of a palladium catalyst, and in the presence or in the absenceof a base.

The coupling reaction can be carried out in a manner similar to Step(c).

Step (h):

Among the compound of the formula II, the compound wherein n is 1 and Xis a carbon atom may be prepared in a method as shown in the followingscheme:

wherein the symbols are as defined above.

Namely, the compound of the formula II may be prepared by the followingsteps: (1) treating the compound of the formula XXII with a halogenatingagent in a suitable solvent or in the absence of a solvent, followed bycondensation of the resultant with the compound of the formula XXI inthe presence of a Lewis acid to give the compound of formula XX, (2)reducing the compound of formula XX, and (3) further reducing thecompound of formula XIX.

The halogenating agent includes a conventional halogenating agent suchas thionyl chloride, phosphorus oxychloride, oxalyl chloride, etc.

The solvent may be any solvent which does not disturb the reaction, andfor example, dichloromethane, carbon tetrachloride, tetrahydrofuran,toluene, etc. may be mentioned.

Further, in the present reaction, the reaction suitably proceeds byadding a catalyst such as dimethylformamide, etc.

The condensation reaction of the compound (XXII) and the compound (XXI)can be carried out according to a conventional method as known asFriedel-Crafts reaction, in the presence of a Lewis acid and in asuitable solvent.

The Lewis acid includes aluminum chloride, boron trifluoride.diethylether complex, tin(IV) chloride, titanium tetrachloride, etc. which areconventionally used in Friedel-Crafts reaction.

The solvent includes halogenated hydrocarbons such as dichloromethane,carbon tetrachloride, dichloroethane, etc.

The reduction of the compound of formula XX can be carried out bytreating the compound (XX) with borohydrides (e.g., sodium borohydride,sodium triacetoxyborohydride, etc.) in a suitable solvent (e.g.,tetrahydrofuran, etc.).

The present reaction can be carried out under cooling or with heating,for example, at a temperature of from −30° C. to 60° C.

The subsequent reduction reaction can be carried out by treating thecompound of formula XIX with a silane reagent (e.g., trialkyl silane,etc.) in a suitable solvent (e.g., acetonitrile, dichloromethane, etc.),in the presence of an acid (e.g., a Lewis acid such as borontrifluoride.diethyl ether complex, etc., and a strong organic acid suchas trifluoroacetic acid, methanesulfonic acid, etc.), or by treatingwith a hydrazine in a suitable solvent (e.g., ethylene glycol, etc.) inthe presence of a base (e.g., potassium hydroxide, etc.).

The present reaction can be carried out under cooling or with heating,for example, at a temperature of from −30° C. to 60° C.

Step (i):

Among the compounds of the formula II, the compound wherein X is anitrogen atom may be prepared by a method as shown in the followingscheme:

wherein R²¹ is a leaving group, and the other symbols are as definedabove.

Examples of the leaving group include a halogen atom such as chlorineatom and bromine atom.

Namely, the compound of the formula II-d may be prepared by condensationof the compound of the formula XXIII with the compound of the formulaXXIV.

The condensation reaction can be carried out in a suitable solvent suchas acetonitrile, etc., in the presence of a base (e.g., an alkali metalhydroxide, such as potassium hydroxide, etc.).

Step (j):

Among the compound of the formula II, the compound wherein Ring A is apyrazole substituted by a lower alkyl group, X is a nitrogen atom and Yis —CH₂— may be prepared by a method as shown in the following scheme:

wherein R²² and R²³ are each independently a lower alkyl group, and theother symbols are as defined above.

Namely, the compound II-e may be prepared by condensation of thecompound of the formula XXV with the compound of the formula XXVI in asuitable solvent (e.g., ethers such as tetrahydrofuran, etc., anaromatic hydrocarbons such as toluene, etc.).

Step (k):

Among the compounds represented by formula (II), a compound wherein Y is—CH₂— group can be prepared by a method as shown in the followingscheme:

wherein the symbols are the same as defined above.

The compound (II-f) can be prepared by condensing a compound of formula(XL) with a compound of formula (XLI), and reducing a compound offormula (XLII).

The condensation reaction can be carried out in a similar manner asdescribed in Step (h). Namely, the condensation reaction can be carriedout in a suitable solvent (e.g., dichloromethane, carbon tetrachloride,dichloroethane, etc.) in the presence of a Lewis acid (e.g., aluminumchloride, zinc chloride, titanium tetrachloride, etc.).

The reduction reaction can be carried out in a similar manner asdescribed in Step (h).

Step (l)

Among the compounds represented by the formula (II), a compound whereinRing B is an isoindolinyl or dihydroisoquinolinyl group can be preparedby a method as shown in the following scheme:

wherein the symbols are the same as defined above.

A compound of formula (II-g) can be prepared by reductive amination of acompound of formula (XLIII) with isoindoline or dihydroisoquinoline.Reductive amination can be carried out in a suitable solvent (e.g.,tetrahydrofuran, acetic acid, dichloroethane, etc.) in the presence of areducing agent such as borohydrides (e.g., sodium borohydride, sodiumtriacetoxyborohydride) and aluminum hydrides (e.g., lithium aluminumhydride).

Further, the compound of the present invention may be converted to eachother within the objective compounds of the present invention. Suchconversion reaction may be carried out according to a conventionalmethod, depending on the kind of the objective substituents. It may bepreferable that functional groups in the compound would be protectedbefore the conversion. The protective groups for the functional groupscan be selected from conventional ones which can be removed by usualmethods.

For example, a compound having as a substituent of Ring B an aryl groupsuch as phenyl group or a heterocyclyl group may be prepared by couplingthe compound in which substituents of the Ring B is a halogen atom suchas a bromine atom, with a suitable phenylboronic acid, phenyltin,hetercyclylboronic acid, or heterocyclyltin.

The coupling reaction may be carried out in a manner similar to Step (c)or Step (g), or in a method as described in the following Examples.

Accordingly, the compound of formula (IA′):

wherein the symbols are the same as defined above, can be prepared by(1) protecting a compound of formula (I-c):

wherein Z is a halogen atom such as chlorine, bromine and iodine atomand R^(A) is the same as defined above, to afford a compound of formula(II-h):

wherein the symbols are the same as defined above, (2) coupling thecompound (II-h) with a compound of formula (XLIV):

wherein R^(x) is B(OH)₂ or an ester thereof, or Sn(lower alkyl)₃, andRing C is the same as defined above, to afford a compound of formula(II-A):

wherein the symbols are the same as defined above, and (3) removing theprotecting groups. Examples of esters of B(OH)₂ include an ester with alower alkyl alcohol such as methanol and ethanol and an ester with alower alkylene diol such as pinacol. Protection of hydroxyl groups canbe carried out by conventional methods. Coupling reaction anddeprotection can be carried out as described in Step (c) or (g) andProcess 1, respectively.

Additionally, the compound of formula (IA′):

wherein the symbols are the same as defined above, can be prepared by(1) converting Z group of a compound of formula (II-h) to B (OH)₂ or anester thereof, (2) coupling said compound with a compound of formula(XLV):

wherein R^(X1) is a halogen atom such as chlorine, bromine and iodineatom and Ring C is the same as defined above, and (3) removing theprotecting groups.

Examples of esters of B (OH)₂ include an ester with a lower alkylalcohol such as methanol and ethanol and an ester with a lower alkylenediol such as pinacol.

Conversion of a halogen atom to B (OH)₂ or an ester thereof can becarried out in a conventional method. For example, conversion of ahalogen atom to B (OH)₂ can be carried out by treating the compound(II-h) with an alkyl lithium such as tert-butyl lithium in a suitablesolvent (e.g., tetrahydrofuran), reacting the resulting compound with atri-alkoxyborane in a suitable solvent (e.g., tetrahydrofuran), andhydrolyzing the resulting compound with an acid (such as acetic acid).And conversion of a halogen atom to an ester of B(OH)₂ can be carriedout by treating the compound (II-h) with an alkyl lithium (such astert-butyl lithium) in a suitable solvent (e.g., tetrahydrofuran),reacting the resulting compound with a tri-alkoxyborane in a suitablesolvent (e.g., tetrahydrofuran), and reacting the resulting compoundwith an appropriate alcohol in a suitable solvent (e.g.,tetrahydrofuran) or without solvent. Coupling reaction and deprotectioncan be carried out as described in Step (c) or (g) and Process 1,respectively.

In the present compound, the compound wherein heteroatom is oxidized(e.g., S-oxide, S,S-oxide, or N-oxide compounds) may be prepared byoxidizing a corresponding S-form or N-form.

The oxidation reaction can be carried out by a conventional method, forexample, by treatment with an oxidizing agent (e.g., peracids such ashydrogen peroxide, m-chloroperbenzoic acid, peracetic acid, etc.) in asuitable solvent (e.g., halogenated hydrocarbons such asdichloromethane, etc.).

The starting compounds of the respective steps described above may beprepared by the methods as disclosed in Reference Examples or a processas mentioned below.

-   (1) Among the compounds of the formula VII, the compound wherein Y    is —CH₂— may be prepared by a method as shown in the following    scheme:

wherein R¹⁵ is a hydrogen atom or a halogen atom, and the other symbolsare as defined above.

Namely, the compound of the formula VII-b may be prepared by couplingthe compound of the formula XXVIII with the compound of the formula XXIXto give the compound of the formula XXVII, followed by reducing theobtained compound of the formula XXVII.

The coupling reaction of the present step may be carried out in a mannersimilar to Step (a). Namely, the compound of the formula XXVIII istreated with an alkyl lithium (e.g., n-butyl lithium, tert-butyllithium, etc.) in a suitable solvent (e.g., diethyl ether,tetrahydrofuran, etc.), followed by reacting the resultant with thecompound of the formula XXIX.

The reduction reaction may be carried out in a manner similar to Step(d), more specifically, by (1) treatment with a silane reagent such astriethylsilane, etc., in a suitable solvent (e.g., acetonitrile,dichloromethane, etc.), at −30° C. to 60° C., in the presence of a Lewisacid such as boron trifluoride.diethyl ether complex or trifluoroaceticacid, (2) treatment with iodotrimethylsilane, or (3) treatment with areducing agent (e.g., borohydrides such as sodium boron hydride, sodiumtriacetoxyborohydride, etc., aluminum hydrides such as lithium aluminumhydride, etc.) in the presence of an acid (e.g., a strong acid such astrifluoroacetic acid, etc., a Lewis acid such as aluminum chloride,etc.).

-   (2) Among the compound of the formula VII, the compound wherein X is    a carbon atom and Y is —CH₂— may be prepared by a method as shown in    the following scheme:

wherein R¹⁶ is a halogen atom, and the other symbols are as definedabove.

The present process may be carried out in a manner similar to Step (h)as mentioned above.

Namely, the compound of the formula VII-c may be prepared by treatingthe compound of the formula XXXIII with a halogenating reagent (e.g.,thionyl chloride, phosphorus oxychloride, oxalyl chloride, etc.) in asuitable solvent (e.g., dichloromethane, carbon tetrachloride,tetrahydrofuran, toluene, etc.) or in the absence of a solvent, to givethe compound of the formula XXXII, subsequently by condensing thiscompound with the compound of the formula XXXI in a suitable solvent(e.g., dichloromethane, carbon tetrachloride, dichloroethane, etc.) inthe presence of a Lewis acid (e.g., aluminum chloride, zinc chloride,titanium tetrachloride, etc.), to give the compound of the formula XXX,and further by reducing the obtained compound.

The reduction reaction can be carried out by treating with a silanereagent (e.g., triethylsilane, etc.) in a suitable solvent (e.g.,acetonitrile, dichloromethane, etc.), in the presence of an acid (e.g.,a Lewis acid such as boron trifluoride.diethyl ether complex, etc., anda strong organic acid such as trifluoroacetic acid, methanesulfonicacid, etc.), or by treating with a hydrazine in a suitable solvent(e.g., ethylene glycol, etc.) in the presence of a base (e.g., potassiumhydroxide, etc.).

-   (3) Among the compounds of the formula VII, the compound wherein X    is a carbon atom and Y is —CH₂— may be prepared by a method as shown    in the following scheme:

wherein R¹⁷ is a lower alkyl group, and the other symbols are as definedabove.

The compound of the formula VII-c may be prepared by coupling thecompound of the formula XXXV with the compound of the formula XXXIV togive the compound of the formula XXX, and subsequently by reducing theobtained compound.

The coupling reaction may be carried out in a manner similar to Step(a). Namely, the compound of the formula (XXV) is lithiated with analkyllithium (e.g., tert-butyl lithium, n-butyl lithium, etc.) in asuitable solvent (e.g., diethyl ether, tetrahydrofuran, etc.), andsubsequently, by reacting the resultant with the compound (XXIV).

The reduction reaction may be carried out in a manner similar to Step(a). Namely, it can be carried out by treating the compound of formulaXXX with a silane reagent (e.g., triethylsilane, etc.) inasuitablesolvent (e.g., acetonitrile, dichloromethane, etc.), in the presence ofan acid (e.g., boron trifluoride.diethyl ether complex, etc).

-   (4) Among the compound of the formula VII, the compound wherein X is    a carbon atom and Y is —CH₂— may be prepared by a method as shown in    the following scheme:

wherein R¹⁸ is a lower alkyl group, and the other symbols are as definedabove.

Namely, the compound of the formula VII-c may be prepared by couplingthe compound of the formula XXVIII with the compound of the formulaXXXVI to give the compound of the formula XXX, and subsequently byreducing the compound.

The present process may be carried out in a manner similar to Step (3).Namely, the compound of the formula (XXVIII) is lithiated with analkyllithium (e.g., tert-butyl lithium, n-butyl lithium, etc.) in asuitable solvent (e.g., diethyl ether, tetrahydrofuran, etc.), andsubsequently, by reacting the resultant with the compound (XXXVI) togive the compound of the formula (XXX). Subsequently, the compound ofthe formula XXX is treated with a silane reagent (e.g., triethylsilane,etc.) in a suitable solvent (e.g., acetonitrile, dichloromethane, etc.)in the presence of an acid (e.g., boron trifluoride.diethyl ethercomplex, etc), to give the compound of the formula (VII-c).

The compound of the formula XIV wherein Ring A is a benzene ring isdisclosed in WO 01/27128 pamphlet.

The compound of the formula VI is disclosed in WO 01/27128 or Benhaddu,S. Czernecki et al., Carbohydr. Res., vol. 260, p. 243-250, 1994.

The compound of the formula VIII may be prepared fromD-(+)-glucono-1,5-lactone according to the method disclosed in U.S. Pat.No. 6,515,117.

The compound of the formula X and the compound of the formula XI may beprepared by the following Reaction Scheme:

wherein the symbols are as defined above.

First, the compound of the formula XXXVII is lithiated with t-butyllithium in a suitable solvent (e.g., tetrahydrofuran, etc.) undercooling (e.g., −78° C.), followed by reacting with trimethyl borate togive the compound of the formula X.

Then, the compound of the formula X is reacted with a 1,2-diol (e.g.,pinacol, etc.) or 1,3-diol (e.g., 2,4-dimethyl-2,4-pentanediol, etc.) togive the compound of the formula XI.

The other starting compounds are commercially available or are describedin WO 01/27128 or WO 2004/080990, or may easily be prepared by astandard method well known to an ordinary skilled person in this field.

Hereinafter, the present invention will be illustrated by Examples andReference Examples, but the present invention should not be construed tobe limited thereto.

EXAMPLE 1 1-(β-D-glucopyranosyl)-3-(5-ethyl-2-thienyl-methyl)benzene

In the above scheme, Me is a methyl group, Et is an ethyl group, TMSOand OTMS are a trimethylsilyloxy group.

-   (1) 3-Bromo-(5-ethyl-2-thienylmethyl)benzene 1 (211 mg) was    dissolved in tetrahydrofuran (2 ml)-toluene (4 ml), and the mixture    was cooled to −78° C. under argon atmosphere. To the mixture was    added dropwise n-butyl lithium (2.44 M hexane solution, 0.29 ml),    and the mixture was stirred at the same temperature for 30 minutes.    Then, a solution of    2,3,4,6-tetrakis-O-trimethylsilyl-D-glucono-1,5-lactone 2 (see U.S.    Pat. No. 6,515,117) (233 mg) in toluene (5 ml) was added dropwise,    and the mixture was further stirred at the same temperature for one    hour to give a lactol compound 3. Without isolating this compound, a    solution of methanesulfonic acid (0.1 ml) in methanol (5 ml) was    added to the reaction solution, and the mixture was stirred at room    temperature overnight. Under ice-cooling, to the mixture was added a    saturated aqueous sodium hydrogen carbonate solution, and the    mixture was extracted with ethyl acetate. The extract was washed    with brine, dried over magnesium sulfate, and the solvent was    evaporated under reduced pressure. The residue was purified by    silica gel column chromatography (chloroform:methanol=19:1) to give    a methyl ether compound 4 (136 mg) of the lactol. APCI-Mass m/Z 412    (M+NH₄).-   (2) A solution of the above methyl ether compound 4 (100 mg) in    dichloromethane (5 ml) was cooled to −78° C. under argon atmosphere,    and thereto were added dropwise successively triisopropylsilane    (0.16 ml), and boron trifluoride.diethyl ether complex (0.10 ml).    The mixture was stirred at the same temperature for 10 minutes, and    warmed. The mixture was stirred at 0° C. for 1 hour and 20 minutes,    and then further stirred at room temperature for 2 hours. Under    ice-cooling, a saturated aqueous sodium hydrogen carbonate solution    was added, and the mixture was extracted with ethyl acetate. The    extract was washed with brine, dried over magnesium sulfate, and the    solvent was evaporated under reduced pressure. The residue was    purified by silica gel column chromatography    (chloroform:methanol=19:1) to give the desired    1-(β-D-glucopyranosyl)-3-(5-ethyl-2-thienylmethyl)benzene 5 (59 mg).    APCI-Mass m/Z 382 (M+NH₄).

EXAMPLE 25-(β-D-glucopyranosyl)-1-(4-ethylphenyl-methyl)-1H-pyridin-2-one

In the above scheme, tBu is a tert-butyl group, OTIPS is atriisopropylsilyloxy group, and the other symbols are as defined above.

-   (1) 5-Bromo-1-(4-ethylphenylmethyl)-1H-pyridin-2-one 6 (293 mg) and    boronic acid ester of glucal 7 (1.0 g) were dissolved in    dimethoxyethane (5 ml). To the mixture were added    bis(triphenyl)phosphine palladium(II) dichloride (35 mg) and 2M    sodium carbonate (2.5 ml), and the mixture was heated with stirring    under reflux under argon atmosphere for 5 hours. The mixture was    cooled to room temperature, and the reaction solution was diluted    with ethyl acetate, and washed with water. The organic layer was    collected, dried over magnesium sulfate, and the solvent was    evaporated under reduced pressure. The residue was purified by    silica gel column chromatography (hexane:ethyl acetate=95:5-70:30)    to give glucal derivative 8 (276 mg) as colorless powder. APCI-Mass    m/Z 654 (M+H).-   (2) A solution of glucal derivative 8 (260 mg) in tetrahydro-furan    (5 ml) was cooled to 0° C. under argon atmosphere, and thereto was    added dropwise a solution of borane.tetrahydrofuran complex (1.13 M    tetrahydrofuran solution, 1.06 ml), and the reaction solution was    stirred at the same temperature overnight. A mixture of an aqueous    hydrogen peroxide solution (31%, 5.0 ml) and 3N aqueous sodium    hydroxide solution (5.0 ml) was added to the reaction solution, and    the mixture was warmed to room temperature, and stirred for 30    minutes. To the mixture was added 20% aqueous sodium thiosulfate    solution (30 ml), and the mixture was extracted with ether. The    extract was washed with brine, dried over magnesium sulfate, and the    solvent was evaporated under reduced pressure. The residue was    purified by silica gel column chromatography (hexane:ethyl    acetate=96:4−66.34) to give C-glucoside compound 9 (59 mg) as    colorless powder. APCI-Mass m/Z 672 (M+H).-   (3) The above C-glucoside compound 9 (55 mg) was dissolved in    tetrahydrofuran (2 ml), and thereto was added tetrabutyl ammonium    fluoride (1.0 M tetrahydrofuran solution, 0.41 ml). The mixture was    heated with stirring under reflux for 3 hours under argon    atmosphere, and the reaction solution was cooled to room    temperature. The solvent was evaporated under reduced pressure, and    the residue was purified by silica gel column chromatography    (chloroform:methanol=100:0-88:12) to give the desired    5-(β-D-glucopyranosyl)-1-(4-ethylphenylmethyl)-1H-pyridin-2-one 10    (10 mg) as colorless powder. APCI-Mass m/Z 376 (M+H).

EXAMPLE 3 1-(β-D-glucopyranosyl)-3-(benzo[b]thiophen-2-ylmethyl)benzene

In the above scheme, Bn is a benzyl group.

-   (1) β-m-Bromophenyl-tetra-O-benzyl-C-glucoside 11 (see WO 01/27128)    (1.00 g) was dissolved in diethyl ether (60 ml), and the mixture was    cooled to −78° C. under argon atmosphere. To the mixture was added    dropwise t-butyl lithium (1.49 M pentane solution, 0.99 ml), and the    mixture was stirred at the same temperature for 10 minutes. Then, a    solution of 2-formylbenzo[b]thiophene (286 mg) in diethyl ether    (2 ml) was added dropwise, and the mixture was further stirred at    the same temperature for 30 minutes. To the reaction mixture was    added a saturated aqueous ammonium chloride solution, and the    mixture was warmed to room temperature. The mixture was extracted    with diethyl ether, the extract was dried over magnesium sulfate,    and the solvent was evaporated under reduced pressure. The residue    was purified by silica gel column chromatography (hexane:ethyl    acetate=90:10-50:50) to give an alcohol compound 12 (835 mg).    APCI-Mass m/Z 780 (M+NH₄).-   (2) A solution of the above alcohol compound 12 (820 mg) in    dichloromethane (15 ml) was cooled to −78° C. under argon    atmosphere, and thereto were added dropwise successively    triethylsilane (0.52 ml), and boron trifluoride.diethyl ether    complex (0.20 ml). The reaction mixture was warmed to room    temperature and stirred at the same temperature for 30 minutes.    Added thereto was a saturated aqueous sodium hydrogen carbonate    solution, and the mixture was extracted with dichloromethane. The    extract was dried over magnesium sulfate, and the solvent was    evaporated under reduced pressure. The residue was purified by    silica gel column chromatography (hexane:ethyl acetate=94:6-75:25)    to give the compound 13 (703 mg). APCI-Mass m/Z 764 (M+NH₄).-   (3) A solution of the above compound 13 (690 mg) in dichloromethane    (20 ml) was cooled to 0° C., and iodotrimethylsilane (0.66 ml) was    added thereto and the mixture was stirred at room temperature for    one hour. Addition of iodotrimethylsilane and stirring at room    temperature were repeated in the same manner for 3 times. Total    amount of the iodotrimethylsilane was summed up to 2.64 ml. Under    ice-cooling, water was added to the reaction mixture, and the    mixture was extracted with diethyl ether twice, and washed with an    aqueous sodium thiosulfate solution. The extract was dried over    magnesium sulfate, and the solvent was evaporated under reduced    pressure. The residue was purified by silica gel column    chromatography (chloroform:methanol=100:0-89:11) to give the desired    1-(β-D-glucopyranosyl)-3-(benzo[b]thiophen-2-ylmethyl)benzene 14    (180 mg). APCI-Mass m/Z 404 (M+NH₄)

EXAMPLE 41-(β-D-glucopyranosyl)-3-(5-chloro-2-thienyl-methyl)-4-methylbenzene

In the above scheme, the symbols are as defined above.

-   (1) A solution of 2-chlorothiophene (447 mg) in tetrahydrofuran    (10 ml) was cooled to −78° C. under argon atmosphere, and thereto    was added dropwise n-butyl lithium (1.59 M hexane solution, 2.61    ml). The mixture was stirred at the same temperature for one hour,    and added dropwise thereto was a solution of    5-bromo-2-methylbenzaldehyde 15 (750 mg) in tetrahydrofuran (5 ml).    The mixture was stirred at the same temperature for 30 minutes to    give a compound 16. Toluene (30 ml) was added, and further added    dropwise thereto was n-butyl lithium (1.59 M hexane solution, 2.37    ml). The mixture was further stirred at the same temperature for 30    minutes, and a solution of    2,3,4,6-tetrakis-O-trimethylsilyl-D-glucono-1,5-lactone 2 (see U.S.    Pat. No. 6,515,117) (1.76 g) in toluene (5 ml) was added dropwise,    and the mixture was further stirred at the same temperature for one    and a half hours to give a lactol compound 17. Subsequently, a    solution of methanesulfonic acid (1.22 ml) in methanol (25 ml) was    added to the reaction solution, and the mixture was stirred at room    temperature overnight. To the mixture was added a saturated aqueous    sodium hydrogen carbonate solution, and the mixture was extracted    with ethyl acetate. The extract was washed with brine, dried over    sodium sulfate, and the solvent was evaporated under reduced    pressure to give a crude methyl ether compound 18, which was used in    the subsequent step without further purification.-   (2) A solution of the above crude methyl ether compound 18 in    dichloromethane (25 ml) was cooled to −78° C. under argon    atmosphere, and thereto were added dropwise successively    triethylsilane (3.01 ml), and boron trifluoride.diethyl ether    complex (2.39 ml). The reaction mixture was warmed to 0° C., and    stirred at the same temperature for 3 hours. Added thereto was a    saturated aqueous sodium hydrogen carbonate solution, and the    mixture was extracted with ethyl acetate. The extract was washed    with brine, dried over sodium sulfate, and the solvent was    evaporated under reduced pressure. The residue was purified by    silica gel column chromatography (chloroform:methanol=100:0-92:8) to    give the desired    1-(β-D-glucopyranosyl)-3-(5-chloro-2-thienylmethyl)-4-methyl-benzene    19 (183 mg). APCI-Mass m/Z 402/404 (M+NH₄).

In a manner similar to the method disclosed in any of the above Examples1 to 4, the compounds shown in Table 1 below were prepared fromcorresponding starting materials. The numbers shown in a column of“preparation method” in the Table indicates the Example number,according to which the preparation was carried out.

TABLE 1

Prepar- ation APCI-Mass Examples Ring A Ring B Method (m/Z) 5

1 416/418 (M + NH₄) 6

1 396 (M + NH₄) 7

1 412 (M + NH₄) 8

1 412 (M + NH₄) 9

3 354 (M + NH₄) 10

3 388/390 (M + NH₄) 11

1 396 (M + NH₄) 12

1 430/432 (M + NH₄) 13

1 426 (M + NH₄) 14

1 382 (M + NH₄) 15

1 416/418 (M + NH₄) 16

1 442/444 (M + NH₄) 17

1 430/432 (M + NH₄) 18

2 444/446 (M + NH₄) 19

1 422/424 (M + NH₄) 20

1 478/480 (M + NH₄) 21

2 470/472 (M + NH₄) 22

1 484/486 (M + NH₄) 23

1 450/452 (M + NH₄) 24

4 436/438 (M + NH₄) 25

1 504/506 (M + NH₄) 26

2 456/458 (M + NH₄) 27

1 448/450 (M + NH₄) 28

1 464/466 (M + NH₄) 29

4 478/480 (M + NH₄) 30

1 434 (M + NH₄) 31

1 438/440 (M + NH₄) 32

1 418 (M + NH₄) 33

1 422 (M + NH₄) 34

1 422 (M + NH₄) 35

1 448 (M + NH₄) 36

1 422 (M + NH₄) 37

1 484 (M + NH₄) 38

1 472 (M + NH₄) 39

1 418 (M + NH₄) 40

1 422 (M + NH₄) 41

2 418 (M + NH₄) 42

1 418 (M + NH₄) 43

1 452/454 (M + NH₄) 44

1 452/454 (M + NH₄) 45

1 472/474 (M + NH₄) 46

1 466/468 (M + NH₄) 47

1 418 (M + NH₄) 48

1 468/470 (M + NH₄) 49

1 472/474 (M + NH₄) 50

2 506/508 (M + NH₄) 51

2 438/440 (M + NH₄) 52

2 456/458 (M + NH₄) 53

2 440 (M + NH₄) 54

2 438/440 (M + NH₄) 55

1 468/470 (M + NH₄) 56

1 468/470 (M + NH₄) 57

2 456/458 (M + NH₄) 58

1 470/472 (M + NH₄) 59

2 456/458 (M + NH₄) 60

2 456/458 (M + NH₄) 61

2 472/474 (M + NH₄) 62

2 440 (M + NH₄) 63

4 452/454 (M + NH₄) 64

2 438/440 (M + NH₄) 65

1 432 (M + NH₄) 66

2 472 (M + NH₄) 67

1 464/466 (M + NH₄) 68

1 478/480 (M + NH₄) 69

1 482/484 (M + NH₄) 70

1 482/484 (M + NH₄) 71

1 508/510 (M + NH₄) 72

1 508/510 (M + NH₄) 73

1 508/510 (M + NH₄) 74

1 448 (M + NH₄) 75

1 492 (M + NH₄) 76

1 492 (M + NH₄) 77

1 466 (M + NH₄) 78

1 482/484 (M + NH₄) 79

1 492 (M + NH₄) 80

1 466 (M + NH₄) 81

1 466 (M + NH₄) 82

1 444 (M + NH₄) 83

1 462 (M + NH₄) 84

1 462 (M + NH₄) 85

2 460 (M + NH₄) 86

1 458 (M + NH₄) 87

1 478/480 (M + NH₄) 88

1 498/500 (M + NH₄) 89

1 478/480 (M + NH₄) 90

1 474 (M + NH₄) 91

2 426 (M + H) 92

2 440 (M + H) 93

2 382 (M + NH₄) 94

2 382 (M + NH₄) 95

2 382 (M + NH₄) 96

2 382 (M + NH₄) 97

2 416/418 (M + NH₄) 98

2 416/418 (M + NH₄) 99

1 404 (M + NH₄) 100

1 366 (M + NH₄) 101

1 388 (M + NH₄) 102

1 422/424 (M + NH₄)

EXAMPLE 1031-(β-D-glucopyranosyl)-3-(benzothiazol-2-yl-methyl)-4-methylbenzene

In the above scheme, the symbols are as defined above.

-   (1) 1-(benzothiazol-2-ylmethyl)-5-bromo-2-methylbenzene 20 (495 mg)    was dissolved in tetrahydrofuran (5 ml)-toluene (10 ml), and the    mixture was cooled to −78° C. under argon atmosphere. To the mixture    was added dropwise n-butyl lithium (2.44 M hexane solution, 0.67    ml), and successively was added dropwise t-butyl lithium (2.44 M    pentane solution, 1.57 ml). The mixture was stirred at the same    temperature for 10 minutes, and then, a solution of    2,3,4,6-tetrakis-O-trimethylsilyl-D-gluconol, 5-lactone 2 (see U.S.    Pat. No. 6,515,117) (2.17 g) in toluene (5 ml) was added dropwise,    and the mixture was further stirred at the same temperature for 15    minutes to give a lactol compound 21. Without isolating this    compound, a solution of methanesulfonic acid (1.5 ml) in methanol    (25 ml) was added to the reaction solution, and the mixture was    stirred at room temperature overnight. Under ice-cooling, to the    mixture was added a saturated aqueous sodium hydrogen carbonate    solution, and the mixture was extracted with ethyl acetate. The    extract was washed with brine, dried over magnesium sulfate, and the    solvent was evaporated under reduced pressure to give a methyl ether    compound 22, which was used in the subsequent step without further    purification.-   (2) A solution of the above methyl ether compound 22 in    dichloromethane (20 ml)-acetonitrile (10 ml) was cooled to −78° C.    under argon atmosphere, and thereto were added dropwise successively    triethylsilane (1.24 ml), and boron trifluoride.diethyl ether    complex (0.99 ml). The mixture was warmed to room temperature and    stirred at the same temperature for 30 minutes. Under ice-cooling, a    saturated aqueous sodium hydrogen carbonate solution was added, and    the solvent was evaporated under reduced pressure. The residue was    extracted with ethyl acetate. The extract was washed with brine,    dried over magnesium sulfate, and the solvent was evaporated under    reduced pressure. The residue was purified by silica gel column    chromatography (chloroform:methanol=100:0-85:15) to give    1-(β-D-glucopyranosyl)-3-(benzothiazol-2-ylmethyl)-4-methylbenzene    23 (200 mg) as colorless powder. APCI-Mass m/Z 402 (M+H).

In a manner similar to Examples 103, the compounds shown in Table 2below were prepared from corresponding starting materials.

TABLE 2

APCI-Mass Examples Ring A Ring B (m/Z) 104

422/424 (M + H) 105

480/482 (M + NH₄)

EXAMPLE 1061-(β-D-glucopyranosyl)-4-chloro-3-(1-oxy-benzo[b]thiophen-2-ylmethyl)benzene

In the above scheme, AcO and OAc are an acetyloxy group.

-   (1) The compound 24 (9.61 g) obtained in Example 31 was dissolved in    chloroform (100 ml), and to the mixture were added acetic anhydride    (21.6 ml), pyridine (18.5 ml), and 4-dimethylaminopyridine (128 mg),    and the mixture was stirred at room temperature for 3.5 days. Then,    Chloroform was evaporated under reduced pressure, and the residue    was dissolved in ethyl acetate (200 ml). The solution was washed    successively with 10% aqueous hydrochloric acid solution, water, a    saturated aqueous sodium hydrogen carbonate solution, and brine,    dried over magnesium sulfate, and treated with activated carbon. The    solvent was evaporated under reduced pressure, and the residue was    crystallized from ethanol to give a tetraacetate compound 25 (6.14    g). APCI-Mass m/Z 606/608 (M+NH₄).-   (2) The above tetraacetate compound 25 (1.00 g) was dissolved in    dichloromethane (20 ml), and under ice-cooling, m-chloroperbenzoic    acid (439 mg) was added thereto, and the mixture was stirred a room    temperature overnight. m-Chloroperbenzoic acid was further added    thereto, and the mixture was stirred again at room temperature    overnight. The reaction mixture was washed successively with 10%    aqueous sodium thiosulfate solution, a saturated aqueous sodium    hydrogen carbonate solution, and brine. The mixture was dried over    magnesium sulfate, and the solvent was evaporated under reduced    pressure. The residue was purified by silica gel column    chromatography (hexane:ethyl acetate=2:1-1:2) to give a sulfoxide    compound 26 (295 mg). APCI-Mass m/Z 622/624 (M+NH₄).-   (3) The above sulfoxide compound 26 (293 mg) was dissolved in a    mixture of methanol (10 ml)-tetrahydrofuran (5 ml), and sodium    methoxide (28% methanol solution, 2 drops) was added thereto, and    the mixture was stirred at room temperature for one hour. The    solvent was evaporated under reduced pressure, and the residue was    purified by silica gel column chromatography    (chloroform:methanol=9:1) to give    1-(β-D-glucopyranosyl)-4-chloro-3-(1-oxybenzo[b]thiophen-2-ylmethyl)benzene    as pale yellow powder. APCI-Mass m/Z 454/456 (M+NH₄).

EXAMPLE 1071-(β-D-glucopyranosyl)-4-chloro-3-(1,1-dioxy-benzo[b]thiophen-2-ylmethyl)benzene

The target compound was prepared in a manner similar to Example 106.APCI-Mass m/Z 470/472 (M+NH₄).

EXAMPLE 1083,5-dimethyl-4-(4-ethylphenylmethyl)-1-(β-D-glucopyranosyl)pyrazole

In the above scheme, the symbols are as defined above.

-   (1) 3-(4-ethylphenylmethyl)-2,4-pentanedione 28 (700 mg) and    2,3,4,6-tetra-O-benzyl-α,β-D-glucosehydrazone 29 (1.70 g)(See    Schmidt, R. R. et al., Liebigs Ann. Chem. 1981, 2309) were dissolved    in tetrahydrofuran (20 ml), and the mixture was stirred at room    temperature for 18 hours under argon atmosphere. The solvent was    evaporated under reduced pressure, and the residue was dissolved in    toluene (20 ml), and the mixture was heated with stirring under    reflux for 2 hours. The mixture was left alone until it was cooled,    and the solvent was evaporated under reduced pressure. The residue    was purified by silica gel column chromatography (hexane:ethyl    acetate=90:10-65:35) to give 3,    5-dimethyl-4-(4-ethylphenylmethyl)-1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)pyrazole    30 (299 mg) as a pale yellow semisolid. APCI-Mass m/Z 737 (M+H).-   (2) The above tetrabenzyl compound 30 (294 mg) was dissolved in a    mixture of ethanol (5 ml) and tetrahydrofuran (4 ml), and added    thereto was palladium hydroxide (100 mg), and the mixture was    stirred at room temperature for 16 hours under hydrogen atmosphere    under normal pressure. Insoluble materials were filtered off, and    the solvent was evaporated under reduced pressure. The residue was    crystallized from diethyl ether to give the desired    3,5-dimethyl-4-(4-ethylphenylmethyl)-1-(β-D-glucopyranosyl) pyrazole    31 (118 mg) as colorless powder. APCI-Mass m/Z 377 (M+H).

EXAMPLE 1094-(4-ethylphenylmethyl)-1-(β-D-glucopyranosyl)-1,2,3-triazole

In the above scheme, n-Bu is n-butyl group, and other symbols are asdefined above.

-   (1) A solution of    4-(bromomethyl)-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosy    1)-1,2,3-triazole 32 (500 mg) (See Federico G. H. et al., J. Med.    Chem. (1979) 29, 496), tri-n-butyl(4-ethylphenyl)tin 33 (604 mg) and    tetrakis(triphenylphosphine)palladium (0) (59 mg) in tetrahydrofuran    (10 ml) was stirred under heating at 70° C. for 12 hours under argon    atmosphere. The reaction mixture was cooled to room temperature,    diluted with ethyl acetate, and then, an aqueous potassium fluoride    solution was added thereto and the mixture was stirred at room    temperature for one hour. Insoluble materials were filtered off, and    the filtrate was washed with water, and dried over magnesium    sulfate. The solvent was evaporated under reduced pressure. The    residue was purified by silica gel column chromatography    (hexane:ethyl acetate=90:10-50:50) to give    4-(4-ethylphenylmethyl)-1-(2,3,4,6-tetra-O-acetyl-β-D-gluco    pyranosyl)-1,2,3-triazole 34 (90 mg) as a colorless solid. APCI-Mass    m/Z 518 (M+H).-   (2) From the above tetraacetate compound 34, the desired    4-(4-ethylphenylmethyl)-1-(β-D-glucopyranosyl)-1,2,3-triazole 35 was    prepared in a manner similar to Example 106-(3) as a colorless    solid.

APCI-Mass m/Z 350 (M+H).

EXAMPLE 110 4-(4-Ethylphenylmethyl)-1-(β-D-glucopyranosyl)pyrazole

In the above scheme, TMS is a trimethylsilyl group, and other symbolsare as defined above.

-   (1) To a solution of 4-(4-ethylphenylmethyl)pyrazole 36 (495 mg) in    acetonitrile (2.0 ml) was added N,O-bis(trimethylsilyl)acetamide    (1.05 ml), and the mixture was stirred under heating at 60° C. for    2.5 hours under argon atmosphere. The reaction mixture was cooled to    room temperature, and the solvent was evaporated under reduced    pressure to give crude    4-(4-ethylphenylmethyl)-1-trimethylsilylpyrazole 37, which was used    in the subsequent reaction without further purification.-   (2) The above N-silyl compound 37 was dissolved in dichloroethane    (7.0 ml), and added thereto were molecular sieve 4A powder (500 mg),    1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose 38 (1.04 g) and    trimethylsilyl trifluoromethanesulfonate (0.51 ml). The mixture was    stirred under heating at heating at 80° C. for 3 hours under argon    atmosphere. The reaction mixture was cooled to room temperature, and    insoluble materials were filtered off. Subsequently, the filtrate    was poured into a saturated aqueous sodium hydrogen carbonate    solution. The mixture was extracted twice with dichloromethane, and    dried over sodium sulfate. The solvent was evaporated under reduced    pressure, and the residue was purified by silica gel column    chromatography (hexane:ethyl acetate=80:20-50:50) to give    4-(4-ethylphenylmethyl)-1-(2,3,4,6-tetra-O-acetyl-β-D-gluco    pyranosyl)pyrazole 39 (610 mg) as a colorless semisolid. APCI-Mass    m/Z 517 (M+H).-   (3) From the above tetraacetate compound 39, the desired    4-(4-ethylphenylmethyl)-1-(β-D-glucopyranosyl)pyrazole 40 was    prepared in a manner similar to Example 106-(3) as colorless oil.    APCI-Mass m/Z 349 (M+H).

In a manner similar to Example 110, the compounds shown in Table 3 belowwere prepared from corresponding starting materials.

TABLE 3

APCI-Mass Examples Ring A (m/Z) 111

363 (M + H) 112

363 (M + H) 113

376 (M + H) 114

393 (M + NH₄) 115

415 (M + NH₄) 116

399 (M + H) 117

399 (M + H)

EXAMPLE 1183-RS-(4-ethylphenylmethyl)-1-(β-D-gluco-pyranosyl)-2,3-dihydroindole

In the above scheme, the symbols are as defined above.

-   (1) To a suspension of potassium hydroxide power (953 mg) and sodium    sulfate (6.0 g) in acetonitrile (50 ml) was added    3-(4-ethylphenylmethy)-1H-indole 41 (500 mg), and the mixture was    stirred at room temperature for one hour under argon atmosphere. To    the reaction mixture was added a solution of    benzylchloro-α-D-glucose 42 (3.0 g) (see Cicchillo R. M. et al.,    Carbohydrate Research (2000) 328,431) in acetonitrile (20 ml), and    the mixture was stirred at room temperature overnight. The reaction    mixture was poured into 2N aqueous hydrochloric acid solution, and    the mixture was extracted with diethyl ether. The extract was washed    with brine, dried over magnesium sulfate, and the solvent was    evaporated under reduced pressure. The residue was purified by    silica gel column chromatography (hexane:ethyl acetate=100:0-85:15)    to give    3-(4-ethylphenylmethyl)-1-(2,3,4,6-tetra-O-benzyl-αβ-D-glucopyranosyl)-1H-indole    43 (1.04 g) as a pale yellow syrup. APCI-Mass m/Z 758 (M+H).-   (3) From the above tetrabenzyl compound 43, the desired    3-RS-(4-ethylphenylmethyl)-1-(β-D-glucopyranosyl)-2,3-dihydroindole    44 was prepared in a manner similar to Example 108-(2) as pale pink    powder. APCI-Mass m/Z 400 (M+H)

EXAMPLE 1191-(β-D-glucopyranosyl)-4-chloro-3-(5-(2-pyrimidinyl)-2-thienylmethyl)benzene

In the above scheme, the symbols are as defined above.

-   (1) To a solution of 5-boromo-2-chlorobenzoic acid 45 (1.22 g) in a    mixture of tetrahydrofuran (20 ml)-toluene (20 ml) was added    dropwise n-butyl lithium (2.44 M hexane solution, 4.26 ml) at    −78° C. under argon atmosphere. The mixture was stirred at −78° C.    for 30 minutes, and added dropwise thereto was a solution of    2,3,4,6-tetra-O-benzyl-β-D-glucolactone 46 (2.16 g) in toluene (10    ml), and the mixture was further stirred at the same temperature for    2 hours. To the mixture was added a saturated aqueous ammonium    chloride solution, and the mixture was warmed to room temperature.    The reaction mixture was made acidic by addition of 10% aqueous    hydrochloric acid solution, and extracted with ethyl acetate. The    extract was washed with brine, and dried over magnesium sulfate. The    solvent was evaporated under reduced pressure to give a crude    compound 47 as oil, which was used in the subsequent step without    further purification.-   (2) The above crude compound 47 was dissolved in dichloromethane (30    ml), and thereto were added dropwise triisopropylsilane (2.46 ml)    and boron trifluoride.diethyl ether complex (1.52 ml) at −78° C.    Subsequently, the mixture was stirred at 0° C. for one hour, and    added there to was a saturated aqueous sodium hydrogen carbonate    solution, and the mixture was further stirred for 20 minutes. The    reaction mixture was made acidic by addition of 10% aqueous    hydrochloric acid solution, and extracted with ethyl acetate. The    extract was washed with brine, and dried over magnesium sulfate. The    solvent was evaporated under reduced pressure, and the residue was    purified by silica gel chromatography    (chloroform:methanol=100:1-50:1) to give a compound 48 (1.41 g) as    oil.-   (3) The compound 48 (1.41 g) was dissolved in dichloromethane (10    ml), and added thereto was oxalyl chloride (2 ml). The mixture was    stirred at room temperature for 3 hours. The solvent was evaporated    under reduced pressure to give a corresponding acid chloride. The    compound was dissolved in chloroform (10 ml), and added dropwise to    a solution of N,O-dimethylhydroxyamine hydrochloride (390 mg) and    triethyl amine (1.12 ml) in chloroform (10 ml) at 0° C. The mixture    was stirred at room temperature overnight, and the reaction mixture    was washed successively with 10% aqueous hydrochloric acid solution,    water, a saturated aqueous sodium hydrogen carbonate solution and    brine. The mixture was dried over magnesium sulfate, and the solvent    was evaporated under reduced pressure. The residue was purified by    silica gel column chromatography (hexane:ethyl acetate=4:1-2:1) to    give a compound 49 (784 mg) as pale yellow oil. APCI-Mass m/Z    739/741 (M+NH₄).-   (4) The compound 49 (1.22 g) was dissolved in tetrahydrofuran (20    ml), and the mixture was cooled to −78° C. under argon atmosphere.    To the mixture was added dropwise diisobutylaluminum hydride (1.0 M    toluene solution, 4.2 ml), and the mixture was stirred at the same    temperature for 3 hours. Added thereto was 10% aqueous hydrochloric    acid solution, and the mixture was extracted with ethyl acetate. The    extract was washed successively with a saturated aqueous sodium    hydrogen carbonate solution and brine. The extract was dried over    magnesium sulfate and the solvent was evaporated under reduced    pressure. The residue was purified by silica gel column    chromatography (hexane:ethyl acetate=9:1) to give a compound 50 (771    mg) as pale yellow oil. APCI-Mass m/Z 680/682 (M+NH₄).-   (5) 2,5-dibromothiophene 51 (1.31 g) was dissolved in    tetrahydrofuran (30 ml) and the mixture was cooled to −78° C. under    argon atmosphere. To the mixture was added dropwise n-butyl lithium    (2.59 M hexane solution, 2.01 ml), and the mixture was stirred at    the same temperature for 30 minutes. Added dropwise thereto was a    solution of the above compound 50 (2.40 g) in tetrahydrofuran (15    ml), and the mixture was stirred at −78° C. for 2 hours. Added    thereto was a saturated aqueous ammonium chloride solution, and the    mixture was extracted with ethyl acetate and washed with brine. The    extract was dried over magnesium sulfate and the solvent was    evaporated under reduced pressure. The residue was purified by    silica gel column chromatography (hexane:ethyl acetate=9:1-4:1) to    give a compound 52 (2.62 mg) as pale brown oil. APCI-Mass m/Z    842/844 (M+NH₄).-   (6) The compound 52 was treated in a manner similar to Example 3-(2)    to give    1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-chlorobenzene    53 as a pale yellow solid. APCI-Mass m/Z 826/828 (M+NH₄)-   (7) A mixed solution of the above    1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-chlorobenzene    53 (200 mg), tri-n-butyl(2-pyrimidinyl)tin 54 (137 mg) and    bis(triphenylphosphine)palladium (II) dichloride (9 mg) in    N-methyl-2-pyrrolidinone (5 ml) was stirred at 100° C. four 7 hours    under argon atmosphere. The mixture was cooled to room temperature,    and water was added thereto, and the mixture was extracted with    ethylacetate. The extract was washed with water and subsequently    with brine, and dried over magnesium sulfate. The solvent was    evaporated under reduced pressure. The residue was purified by    silica gel column chromatography (hexane:ethyl acetate=4:1-2:1) to    give    1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-4-chloro-3-(5-(2-pyrimidinyl)-2-thienylmethyl)benzene    55 (93 mg) as pale brown oil. APCI-Mass m/Z 826/828 (M+NH₄).-   (8) To a solution of the above    1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-4-chloro-3-(5    (2-pyrimidinyl)-2-thienylmethyl)benzene 55 (90 mg) in ethanethiol    (1.5 ml) was added boron trifluoride ether complex (0.42 ml) at 0°    C., and the mixture was stirred at room temperature overnight. The    mixture was cooled again to 0° C., and added thereto were a    saturated aqueous sodium hydrogen carbonate solution and an aqueous    sodium thiosulfate solution. The mixture was extracted with ethyl    acetate and tetrahydrofuran, and the extract was dried over    magnesium sulfate. The solvent was evaporated under reduced    pressure. The residue was purified by silica gel column    chromatography (chloroform:methanol=19:1-9:1) to give the desired    1-(β-D-glucopyranosyl)-4-chloro-3-(5-(2-pyrimidinyl)-2-thienylmethyl)benzene    56 (27 mg) as pale yellow powder. APCI-Mass m/Z 449/451 (M+H).

EXAMPLE 1201-(β-D-glucopyranosyl)-3-(5-(6-fluoro-3-pyridyl)-2-thienyl-methyl)-4-methylbenzene

In the above scheme, the symbols are as defined as above.

-   (1) The compound 19 obtained in Example 4 was treated in a manner    similar to Example 106—(1) to give    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-chloro-2-thienylmethyl)-4-methylbenzene    57 as colorless crystals. APCI-Mass m/Z 570/572 (M+NH₄).-   (2) A solution of the above    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-chloro-2-thienylmethyl)-4-methylbenzene    57 (200 mg), 6-fluoropyridine-3-boronic acid 58 (117 mg),    tri-tert-butylphosphine-tetrafluoroboric acid adduct (24 mg),    potassium fluoride (80 mg) and tris(dibenzylideneacetone)    dipalladium (0) (27 mg) in tetrahydrofuran (8 ml) was stirred at    room temperature for 2 days under argon atmosphere. Added thereto    was a saturated aqueous ammonium chloride solution and the mixture    was extracted with ethyl acetate. The extract was dried over    magnesium sulfate. The solvent was evaporated under reduced pressure    and the residue was purified by silica gel column chromatography    (hexane:ethyl acetate=90:10-70:30) to give    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(6-fluoro-3-pyridyl)-2-thienylmethyl)-4-methylbenzene    59 (44 mg) as colorless crystals. APCI-Mass m/Z 631 (M+NH₄).-   (3) The above    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(6-fluoro-3-pyridyl)-2-thienylmethyl)-4-methylbenzene    59 (39 mg) was dissolved in 1,4-dioxane (4 ml)-tetrahydrofuran (4    ml), and added thereto was 2N sodium hydroxide (2 ml). The mixture    was stirred at room temperature for one hour. The mixture was made    acidic by addition of an aqueous citric acid solution, and the    mixture was extracted with ethyl acetate. The extract was washed    successively with a saturated aqueous sodium hydrogen carbonate    solution and brine, and then dried over sodium sulfate. The solvent    was evaporated under reduced pressure to give the desired    1-(β-D-glucopyranosyl)-3-(5-(6-fluoro-3-pyridyl)-2-thienyl-methyl)-4-methylbenzene    60 (34 mg) as colorless powder. APCI-Mass m/Z 463 (M+NH₄).

EXAMPLE 1211-(β-D-glucopyranosyl)-4-chloro-3-(2-(5-phenyl-2-thienyl)-ethyl)benzene

The target compound was obtained in a manner similar to Example 1, from5-bromo-2-chloro-1-(2-(5-phenyl-2-thienyl)ethyl)-benzene. APCI-Mass m/Z478/480 (M+NH₄).

EXAMPLE 1221-(β-D-glucopyranosyl)-3-(5-(3-dimethylaminophenyl)-2-thienylmethyl)-4-methylbenzene

-   (1)    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-chloro-2-thienylmethyl)-4-methylbenzene    57 obtained in Example 120 (1) and 3-dimethylaminophenyl boronic    acid were used and treated in a manner similar to Example 120—(2) to    give    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(3-dimethylaminophenyl)-2-thienylmethyl)-4-methyl-benzene.    APCI-Mass m/Z 638 (M+H).-   (2) the above    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(3-dimethylaminophenyl)-2-thienylmethyl)-4-methyl-benzene    was treated in a manner similar to Example 106-(3) to give the    target compound. APCI-Mass m/Z 470 (M+H).

EXAMPLE 1231-(β-D-glucopyranosyl)-4-chloro-3-(5-(3-cyanophenyl)-2-thienylmethyl)benzene

-   (1) A mixed solution of    1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-chlorobenzene    53 (1.24 g) obtained in Example 119-(6), 3-cyanophenylboronic acid    (270 ml), bis(triphenylphosphine)palladium (II) dichloride (54 mg)    and 2M aqueous sodium carbonate solution (2.3 ml) in    1,2-dimethoxyethane (12 ml) was heated under reflux for 4 hours. The    mixture was diluted with ethyl acetate and washed successively with    a saturated aqueous sodium hydrogen carbonate solution and brine.    The mixture was dried over sodium sulfate, and the solvent was    evaporated under reduced pressure. The residue was purified by    silica gel column chromatography (hexane:ethyl acetate=7:1-5:1) to    give    1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-4-chloro-3-(5-(3-cyanophenyl)-2-thienylmethyl)benzene    (1.12 g) as colorless oil. APCI-Mass m/Z 849/851 (M+NH₄).-   (2) The above    1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-4-chloro-3-(5-(3-cyanophenyl)-2-thienylmethyl)benzene    was used and treated in a manner similar to Example 3-(3) to give    the target compound as colorless powder. APCI-Mass m/Z 489/491    (M+NH₄).

EXAMPLE 1241-(β-D-glucopyranosyl)-4-methyl-3-(5-(5-pyrimidinyl)-2-thienylmethyl)benzene

-   (1) A mixed solution of    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-chloro-2-thienylmethyl)-4-methylbenzene    57 (600 mg) obtained in Example 120-(1),    tri-n-butyl(5-pyrimidinyl)tin (600 mg),    tri-tert-butylphosphine.tetrafluoroboric acid adduct (116 mg),    cesium fluoride (414 mg), and    tris(dibenzylideneacetone)dipalladium (0) (91 mg) in 1,4-dioxane    (18 ml) was heated under reflux at 100° C. for 3 hours under argon    atmosphere. Insoluble materials were filtered off, and the filtrate    was diluted with ethyl acetate and washed with brine. The solvent    was evaporated under reduced pressure, and the residue was purified    by silica gel column chromatography (hexane:ethyl    acetate=75:25-40:60) to give    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-methyl-3-(5    (5-pyrimidinyl)-2-thienylmethyl)benzene (266 mg) as colorless    crystals. APCI-Mass m/Z 597 (M+H).-   (2) The above    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-methyl-3-(5    (5-pyrimidinyl)-2-thienylmethyl)benzene was used and treated in a    manner similar to Example 106-(3) to give the target compound as    colorless powder. APCI-Mass m/Z 429 (M+H)

EXAMPLE 1251-(β-D-glucopyranosyl)-4-chloro-3-(2-phenyl-5-thiazolyl-methylbenzene

The target compound was prepared in a manner similar to Example 1,starting from 5-bromo-2-chloro-1-(2-phenyl-5-thiazolylmethyl)benzene.APCI-Mass m/Z 448/450 (M+H).

EXAMPLE 1261-(β-D-glucopyranosyl)-4-chloro-3-(5-(3-pyridyl)-2-thienyl-methyl)benzene

-   (1)    1-(β-D-glucopyranosyl)-4-chloro-3-(5-chloro-2-thienylmethyl)benzene    obtained in Example 19 was used and treated in a manner similar to    Example 106-(1) to give    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)₄-chloro-3-(5-chloro-2-thienylmethyl)benzene    as colorless crystals. APCI-Mass m/Z 590/592 (M+NH₄).-   (2) The above    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-chloro-2-thienylmethyl)benzene    and tri-n-butyl(3-pyridyl)tin were used and treated in a manner    similar to Example 124 to give the target compound as colorless    powder. APCI-Mass m/Z 448/450 (M+H)

EXAMPLE 1271-(β-D-glucopyranosyl)-3-(5-(3-cyanophenyl)-2-thienyl-methyl)-4-methylbenzene

-   (1)    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-chloro-2-thienylmethyl)-4-methylbenzene    57 obtained in Example 120-(1) and 3-cyanophenylboronic acid were    used and treated in a manner similar to Example 120—(2) to give    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(3-cyano    phenyl)-2-thienylmethyl)-4-methylbenzene. APCI-Mass m/Z 637 (M+NH₄).-   (2) The above    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(3-cyano    phenyl)-2-thienylmethyl)-4-methylbenzene was used and treated in a    manner similar to Example 106—(3) to give the target compound as    colorless powder. APCI-Mass m/Z 469 (M+NH₄)

EXAMPLE 1281-(β-D-glucopyranosyl)-4-chloro-3-(5-pyrazinyl-2-thienyl-methyl)benzene

In the above scheme, the symbols are as defined above.

-   (1) A solution of mesityl bromide (4.74 g) in tetrahydrofuran    (100 ml) was cooled to −78° C. under argon atmosphere, and thereto    was added dropwise t-butyl lithium (1.43 M pentane solution, 33 ml).    The mixture was stirred at −30 to −20° C. for one hour, and then, a    mixed solution of t-butyl 5-bromo-2-chlorobenzoate 61 (4.94 g) and    2,3,4,6-tetrakis-O-trimethylsilyl-D-glucono-1,5-lactone 2 (see U.S.    Pat. No. 6,515,117) (11.10 g) in tetrahydrofuran (70 ml) was added    dropwise thereto at −78° C. The mixture was stirred at the same    temperature for one hour to give a compound 62. Without isolating    this compound, a solution of methanesulfonic acid (3.75 ml) in    methanol (50 ml) was added to the reaction solution, and the mixture    was stirred at room temperature for 18 hours. To the mixture was    added a saturated aqueous sodium hydrogen carbonate solution at 0°    C., and the mixture was extracted with ethyl acetate twice. The    extract was washed with brine, dried over magnesium sulfate, and the    solvent was evaporated under reduced pressure. The residue was    purified by silica gel column chromatography    (chloroform:methanol=19:1) to give a methyl ether compound 63    (4.55 g) of the lactol as pale yellow powder. APCI-Mass m/Z 422/424    (M+NH₄).-   (2) The compound 63 was treated in a manner similar to Example    106-(1) to give the compound 64. APCI-Mass m/Z 590/592 (M+NH₄).-   (3) A solution of the above compound 64 (7.10 g) in formic acid    (50 ml) was stirred at 50° C. for 30 minutes. The solvent was    evaporated under reduced pressure, and the residue was subjected to    azeotropic distillation with toluene, twice, to give a compound 65    as colorless powder. Without further purification, this compound was    dissolved in dichloromethane (50 ml). Added thereto were oxalyl    chloride (1.3 ml) and N,N-dimethylformamide (one drop), and the    mixture was stirred at room temperature overnight. The solvent was    evaporated under reduced pressure to give a corresponding acid    chloride, which was dissolved in dichloroethane (50 ml), without    further purification. To the solution was added 2-bromothiophene 66    (2.63 g) and the mixture was cooled to 0° C. Added gradually thereto    was aluminum chloride (8.26 g), and subsequently, the mixture was    stirred at the same temperature for 30 minutes. The reaction mixture    was poured into ice-cold water, and the mixture was extracted with    ethyl acetate. The extract was washed successively with water, a    saturated aqueous sodium hydrogen carbonate solution and brine,    dried over sodium sulfate, and the solvent was evaporated under    reduced pressure. The residue was purified by silica gel column    chromatography (hexane:ethyl acetate=10:1-5:1) to give a compound 67    (7.01 g) as pale yellowish powder. APCI-Mass m/Z 678/680 (M+NH₄).-   (4) The above ketone compound 67 (7.01 g) was dissolved in ethanol    (50 ml), and thereto was added sodium borohydride (401 mg), and the    mixture was stirred at room temperature for 30 minutes. The solvent    was evaporated under reduced pressure, and the residue was dissolved    in ethyl acetate. The solution was washed with successively with    water, 2N aqueous hydrochloride acid solution, a saturated aqueous    sodium hydrogen carbonate solution and brine, and dried over sodium    sulfate. The solvent was evaporated under reduced pressure to give a    compound 68 as pale yellow powder, which was dissolved in methanol    (50 ml) without further purification. To the solution, sodium    methoxide (28% methanol solution, 5 drops) was added, and then the    mixture was stirred at room temperature for 2.5 hours. The solvent    was evaporated under reduced pressure to give a deacetylated    compound 69 as pale yellow powder. Without further purification, it    was dissolved in dichloromethane (170 ml)-acetonitrile (70 ml), and    added thereto was triethylsilane (10.2 ml), and the mixture was    cooled to 0° C. Added dropwise thereto was boron trifluoride.diethyl    ether complex (8.1 ml), and the mixture was stirred at room    temperature for 5 hours. To the mixture was added a saturated    aqueous sodium hydrogen carbonate solution, and the mixture was    extracted with ethyl acetate, and the extract was dried over    magnesium sulfate. The solvent was evaporated under reduced pressure    to give a crude    1-(β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-chloro benzene    70 as pale brown powder. Without further purification, this was    dissolved in dichloromethane (30 ml), and added thereto were acetic    anhydride (10.0 ml), pyridine (8.57 ml) and 4-dimethylaminopyridine    (258 mg), and the mixture was stirred at room temperature for one    hour. The solvent was evaporated under reduced pressure, and the    residue was dissolved in ethyl acetate, and the solution was washed    successively with water, 1N aqueous hydrochloric acid solution, a    saturated aqueous sodium hydrogen carbonate solution and brine. The    solution was dried over sodium sulfate, and the solvent was    evaporated under reduced pressure. The residue was crystallized from    methanol to give    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-chlorobenzene    71 (3.17 g) as colorless crystals. APCI-Mass m/Z 634/636 (M+NH₄).-   (5) The above    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)4-chlorobenzene    71 (600 mg) was dissolved in 1,4-dioxane (11 ml). Added thereto were    tri-n-butyl(pyrazinyl)tin 72 (720 mg),    tetrakis(triphenylphosphine)palladium (0) (206 mg) and copper (I)    iodide (51 mg), and the mixture was stirred under heating at 100° C.    for 1.5 hours, under irradiation by a microwave (500 W). The mixture    was diluted with ethyl acetate, the insoluble materials were    filtered off, and the filtrate was washed with water. The solvent    was evaporated under reduced pressure. The residue was purified by    silica gel column chromatography (hexane:ethyl acetate=75:25-30:70),    and crystallized from hexane-diethyl ether to give    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-pyrazinyl-2-thienylmethyl)benzene    73 (263 mg) as pale yellow crystals. APCI-Mass m/Z 617/619 (M+H).-   (6) The above    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-pyrazinyl-2-thienylmethyl)benzene    73 was used and treated in a manner similar to Example 106-(3) to    give the desired    1-(β-D-glucopyranosyl)-4-chloro-3-(5-pyrazinyl-2-thienyl-methyl)benzene    74 as colorless powder. APCI-Mass m/Z 449/451 (M+H).

EXAMPLE 1291-(β-D-glucopyranosyl)-4-chloro-3-(6-ethoxy-benzo[b]thiophen-2-ylmethyl)benzene

5-Bromo-2-chloro-1-(6-ethoxybenzo[b]thiophen-2-ylmethyl)-benzene wasused and treated in a manner similar to Example 1 to give the targetcompound. APCI-Mass m/Z 482/484 (M+NH₄).

EXAMPLE 1301-(β-D-glucopyranosyl)-3-(5-(3-difluoromethylphenyl)-2-thienylmethyl)-4-methylbenzene

-   (1)    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-chloro-2-thienylmethyl)-4-methylbenzene    57 obtained in Example 120—(1) and 3-formylphenylboronic acid were    used and treated in a manner similar to Example 120-(2) to give    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(3-formylphenyl)-2-thienylmethyl)-4-methylbenzene.    APCI-Mass m/Z 640 (M+NH₄).-   (2) The above    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)3-(5-(3-formylphenyl)-2-thienylmethyl)-4-methylbenzene    (100 mg) was dissolved in dichloromethane (2 ml), and added thereto    was (diethylamino) sulfur trifluoride (0.30 ml). The mixture was    stirred at room temperature overnight. Water was added to the    mixture and the mixture was extracted with chloroform. The extract    was washed with brine and dried over magnesium sulfate, and then,    the solvent was evaporated under reduced pressure. The residue was    purified by silica gel column chromatography (hexane:ethyl    acetate=9:1-1:1) to give    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(3-difluoromethylphenyl)-2-thienylmethyl)-4-methyl-benzene    (82 mg). APCI-Mass m/Z 662 (M+NH₄).-   (3) The above obtained    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(3-difluoromethylphenyl)-2-thienyl    methyl)-4-methylbenzene was used and treated in a manner similar to    Example 120-(3) to give the desired    1-(β-D-glucopyranosyl)-3-(5-(3-difluoromethylphenyl)-2-thienylmethyl)-4-methylbenzene    as colorless powder.

APCI-Mass m/Z 494 (M+NH₄).

EXAMPLE 1311-(β-D-glucopyranosyl)-4-chloro-3-(6-phenyl-3-pyridyl-methyl)benzene

5-Bromo-2-chloro-1-(6-phenyl-3-pyridylmethyl)benzene was used andtreated in a manner similar to Example 1 to give the target compound.APCI-Mass m/Z 442/444 (M+H).

In a manner similar to the method disclosed in any of the aboveExamples, the compounds shown in Table 4 below were prepared fromcorresponding starting materials. The numbers shown in a column of“preparation method” in the Table indicates the Example number,according to which the preparation was carried out in the similarmanner.

TABLE 4

Preparation APCI-Mass Examples Ring A R^(4a) Method (m/Z) 132

1 512 (M + NH₄) 133

1 512 (M + NH₄) 134

4 472 (M + NH₄) 135

4 458 (M + NH₄) 136

4 486 (M + NH₄) 137

C1 1 456/458 (M + NH₄) 138

2 458 (M + NH₄) 139

2 498 (M + NH₄) 140

1 472 (M + NH₄) 141

1 428 (M + H) 142

4 488/490 (M + NH₄) 143

1 428 (M + H) 144

1 474 (M + NH₄) 145

1 488 (M + NH₄) 146

1 463 (M + NH₄) 147

CF₃ 1 436 (M + NH₄) 148

1 468 (M + NH₄) 149

1 462 (M + NH₄) 150

103 484 (M + H) 151

124 469 (M + NH₄) 152

122 498/500 (M + H) 153

128 454/456 (M + H) 154

2 470/472 (M + NH₄) 155

122 489/491 (M + NH₄) 156

122 466/468 (M + H)

EXAMPLE 1571-(β-D-glucopyranosyl)-4-chloro-3-(6-isopropyloxybenzo[b]thiophen-2-ylmethyl)benzene

5-Bromo-2-chloro-1-(6-isopropyloxybenzo[b]thiophen-2-yl-methyl)benzenewas treated in a manner similar to Example 1 to give the targetcompound. APCI-Mass m/Z 496/498 (M+NH₄).

EXAMPLE 158 1-(β-D-glucopyranosyl)-4-methyl-3-(2-thienylmethyl)benzene

-   (1)    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-chloro-2-thienylmethyl)-4-methylbenzene    57 (12.0 g) obtained in Example 120-(1) was dissolved in    tetrahydrofuran (120 ml) and methanol (360 ml), and added thereto    were triethylamine (24.2 ml) and 10% palladium carbon catalyst (wet,    3.6 g), and the mixture was stirred at room temperature for 18 hours    under hydrogen atmosphere under normal pressure. The insoluble    materials were filtered off, washed with tetrahydrofuran, and the    filtrate was evaporated under reduced pressure. The residue was    dissolved in chloroform, washed successively with a 5% aqueous    citric acid solution, a saturated aqueous sodium hydrogen carbonate    solution and water, and dried over sodium sulfate. The solvent was    evaporated under reduced pressure, and the residue was    recrystallized from ethanol to give    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-methyl-3-(2-thienylmethyl)benzene    (7.79 g) as colorless crystals. APCI-Mass m/Z 536 (M+NH₄).-   (2) The above    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-methyl-3-(2-thienylmethyl)benzene    was treated in a manner similar to Example 106-(3) to give the    desired 1-(β-D-glucopyranosyl)-4-methyl-3-(2-thienyl-methyl)benzene    as colorless powder. APCI-Mass m/Z 368 (M+NH₄)

EXAMPLE 1591-(β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-methylbenzene

-   (1)    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-methyl-3-(2-thienylmethyl)benzene    (11.08 g) obtained in Example 158-(1) was dissolved in chloroform    (100 ml), and added dropwise thereto at 0° C. was a solution of    bromine (3.71 g) in chloroform (13 ml). The mixture was stirred at    0° C. for 1.5 hours, and then, at room temperature for 1 hour, and    the mixture was poured into a 10% aqueous sodium thiosulfate    solution and a saturated aqueous sodium hydrogen carbonate solution.    The mixture was extracted twice with chloroform, washed with brine,    and dried over magnesium sulfate. The solvent was evaporated under    reduced pressure, and the residue was purified by silica gel column    chromatography (hexane:ethyl acetate=80:20-67:33) to give    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-methylbenzene    (7.13 g) as a colorless solid. APCI-Mass m/Z 614/616 (M+NH₄).-   (2) The above    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-methylbenzene    was treated in a manner similar to Example 106—(3) to give the    desired    1-(β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-methylbenzene    as colorless powder. APCI-Mass m/Z 446/448 (M+NH₄).

EXAMPLE 160 1-(β-D-glucopyranosyl)-3-(5-phenyl-2-thienylmethyl)benzene

2-Phenylthiophene and 3-bromobenzadlehyde was treated in a mannersimilar to Example 4 to give the target compound. APCI-Mass m/Z 430(M+NH₄).

EXAMPLE 1611-(β-D-glucopyranosyl)-3-(5-cyano-2-thienylmethyl)-4-methylbenzene

-   (1)    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-methylbenzene    (500 mg) obtained in Example 159-(1) was dissolved in    N,N-dimethylacetamide (10 ml), and added thereto were zinc cyanide    (98 mg), tris(dibenzylideneacetone)dipalladium(0) (77 mg),    1,1′-bis(diphenylphosphino)ferrocene (47 mg) and zinc power (14 mg).    The mixture was heated under stirring at 120° C. overnight. The    reaction solution was cooled, diluted with ethyl acetate and water,    and the insoluble materials were filtered off. The organic layer of    the filtrate was washed twice with water and successively washed    with brine. After drying the same over sodium sulfate, the solvent    was evaporated under reduced pressure, and the residue was purified    by silica gel column chromatography (hexane:ethyl    acetate=100:0-50:50) to give    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-cyano-2-thienylmethyl)-4-methylbenzene    (207 mg) as colorless crystals. APCI-Mass m/Z 561 (M+NH₄)-   (2) The above    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-cyano-2-thienylmethyl)-4-methylbenzene    was treated in a manner similar to Example 106-(3) to give the    desired    1-(β-D-glucopyranosyl)-3-(5-cyano-2-thienylmethyl)-4-methylbenzene    as colorless powder. APCI-Mass m/Z 393 (M+NH₄).

EXAMPLE 1621-(β-D-glucopyranosyl)-4-fluoro-3-(5-(2-pyridyl)-2-thienylmethyl)naphthalene

4-Bromo-1-fluoro-2-(5-(2-pyridyl)-2-thienylmethyl)naphthale was treatedin a manner similar to Example 1 to give the target compound. APCI-Massm/Z 482 (M+H).

EXAMPLE 1631-(β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-chlorobenzene

1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-chlorobenzene71 obtained in Example 128-(4) was treated in a manner similar toExample 106-(3) to give the target compound. APCI-Mass m/Z 466/468(M+NH₄).

EXAMPLE 1641-(β-D-glucopyranosyl)-4-methyl-3-(5-(2-pyrimidinyl)-2-thienylmethyl)benzene

1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-methylbenzeneobtained in Example 159-(1) and tri-n-butyl(2-pyrimidinyl)tin 54 weretreated in a manner similar to Example 128-(5) and (6) to give thetarget compound. APCI-Mass m/Z 429 (M+H).

EXAMPLE 1651-(β-D-glucopyranosyl)-4-methyl-3-(5-(2-thiazolyl)-2-thienylmethyl)benzene

1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-methylbenzeneobtained in Example 159-(1) and tri-n-butyl(2-thiazolyl)tin were treatedin a manner similar to Example 128-(5) and (6) to give the targetcompound. APCI-Mass m/Z 434 (M+H).

EXAMPLE 1661-(β-D-glucopyranosyl)-4-chloro-3-(6-ethyl-3-pyridylmethyl)benzene

5-Bromo-2-chloro-1-(6-ethyl-3-pyridylmethyl)benzene was treated in amanner similar to Example 1 to give the target compound. APCI-Mass m/Z394/396 (M+H).

EXAMPLE 1671-(β-D-glucopyranosyl)-4-chloro-3-(6-ethylbenzo[b]thiophen-2-ylmethyl)benzene

6-Ethylbenzo[b]thiophene and 5-bromo-2-chlorobenzaldehyde obtained inReference Example 16-(1) were treated in a manner similar to Example 4to give the target compound. APCI-Mass m/Z 466/468 (M+H).

EXAMPLE 1681-(β-D-glucopyranosyl)-4-chloro-3-(5-(6-fluoro-3-pyridyl)-2-thienylmethyl)benzene

-   (1)    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-chlorobenzene    71 (500 mg) obtained in Example 128-(4) was dissolved in    1,2-dimethoxyethane (15 ml), and added thereto were    6-fluoropyridine-3-boronic acid 58 (228 mg),    tetrakis(triphenylphosphine)palladium(0) (94 mg) and cesium fluoride    (738 mg). The mixture was heated under reflux for 30 minutes. The    reaction solution was poured into a saturated aqueous sodium    hydrogen carbonate solution and the mixture was extracted with ethyl    acetate. The extract was washed with brine and dried over magnesium    sulfate, and the solvent was evaporated under reduced pressure. The    residue was purified by silica gel column chromatography    (hexane:ethyl acetate=75:25-60:40) to give    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(6-fluoro-3-pyridyl)-2-thienylmethyl)benzene    (454 mg) as a colorless solid. APCI-Mass m/Z 634/636 (M+H).-   (2) The above    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(6-fluoro-3-pyridyl)-2-thienylmethyl)benzene    was treated in a manner similar to Example 106—(3) to give the    desired    1-(β-D-glucopyranosyl)-4-chloro-3-(5-(6-fluoro-3-pyridyl)-2-thienylmethyl)benzene    as colorless powder. APCI-Mass m/Z 483 (M+NH₄), 466 (M+H).

EXAMPLE 1691-(β-D-glucopyranosyl)-4-chloro-3-(5-(6-methoxy-3-pyridyl)-2-thienylmethyl)benzene

1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-chlorobenzene71 obtained in Example 128-(4) and 6-methoxypyridine-3-boronic acid weretreated in a manner similar to Example 168 to give the target compound.APCI-Mass m/Z 478/480 (M+H).

EXAMPLE 1701-(β-D-glucopyranosyl)-4-chloro-3-(5-(6-methoxy-2-pyridyl)-2-thienylmethyl)benzene

1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-chlorobenzene71 obtained in Example 128-(4) and tri-n-butyl(6-methoxy-2-pyridyl)tin(see Gros, Philippe; Fort, Yves. Synthesis (1999), 754-756) were treatedin a manner similar to Example 128-(5) and (6) to give the targetcompound. APCI-Mass m/Z 478/480 (M+H).

EXAMPLE 1711-(β-D-glucopyranosyl)-4-chloro-3-(1-oxo-2-isoindolinylmethyl)benzene

5-Bromo-2-chloro-1-(1-oxo-2-isoindolynilmethyl)benzene was treated in amanner similar to Example 2 to give the target compound. APCI-Mass m/Z437/439 (M+NH₄).

EXAMPLE 1721-(β-D-glucopyranosyl)-4-chloro-3-(1-phenyl-4-pyrazolylmethyl)benzene

5-Bromo-2-chloro-1-(1-phenyl-4-pyrazolylmethyl)benzene was treated in amanner similar to Example 1 to give the target compound. APCI-Mass m/Z431/433 (M+H).

EXAMPLE 1731-(β-D-glucopyranosyl)-4-chloro-3-(5-(6-ethoxy-2-pyridyl)-2-thienylmethyl)benzene

-   (1)    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-chlorobenzene    71 obtained in Example 128-(4) and    tri-n-butyl(6-ethoxy-2-pyridyl)tin (see WO 00/74681) were treated in    a manner similar to Example 128-(5) to give    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(6-ethoxy-2-pyridyl)-2-thienylmethyl)benzene    as colorless crystals. APCI-Mass m/Z 660/662 (M+H).-   (2) The above    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(6-ethoxy-2-pyridyl)-2-thienylmethyl)benzene    (245 mg) was dissolved in tetrahydrofuran (5 ml), added thereto was    a solution of sodium hydride (oil, 9 mg) in ethanol (5 ml), and the    mixture was stirred at room temperature for 2 hours. The solvent was    evaporated under reduced pressure and the residue was purified by    silica gel column chromatography (chloroform:methanol=100:0-90:10)    to give the desired    1-(β-D-glucopyranosyl)-4-chloro-3-(5-(6-ethoxy-2-pyridyl)-2-thienylmethyl)benzene    (145 mg) as colorless powder. APCI-Mass m/Z 492/494 (M+H).

EXAMPLE 1741-(β-D-glucopyranosyl)-4-chloro-3-(6-n-propyloxybenzo[b]thiophen-2-ylmethyl)benzene

5-Bromo-2-chloro-1-(6-n-propyloxybenzo[b]thiophen-2-yl-methyl)benzenewas treated in a manner similar to Example 1 to give the targetcompound. APCI-Mass m/Z 496/498 (M+NH₄).

EXAMPLE 1751-(β-D-glucopyranosyl)-4-chloro-3-(6-(2-fluoroethyloxy)benzo[b]thiophen-2-ylmethyl)benzene

5-Bromo-2-chloro-1-(6-(2-fluoroethyloxy)benzo[b]thiophen-2-ylmethyl)benzenewas treated in a manner similar to Example 1 to give the targetcompound. APCI-Mass m/Z 500/502 (M+NH₄).

EXAMPLE 1761-(β-D-glucopyranosyl)-3-(5-(4-difluoromethylphenyl)-2-thienylmethyl)-4-methylbenzene

-   (1)    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-methylbenzene    from Example 159-(1) and 4-formylphenylboronic acid were treated in    a manner similar to Example 168-(1) to give    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(4-formylphenyl)-2-thienylmethyl)-4-methylbenzene    as a colorless solid. APCI-Mass m/Z 640 (M+NH₄).-   (2) The above    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(4-formylphenyl)-2-thienylmethyl)-4-methylbenzene    was treated in a manner similar to Example 130—(2) to give the    desired    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(4-difluoromethylphenyl)-2-thienyl-methyl)-4-methylbenzene    as colorless crystals. APCI-Mass m/Z 662 (M+NH₄).-   (3) The above    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(4-difluoromethylphenyl)-2-thienylmethyl)-4-methylbenzene    was treated in a manner similar to Example 106-(3) to give the    desired    1-(β-D-glucopyranosyl)-3-(5-(4-difluoromethylphenyl)-2-thienylmethyl)-4-methyl-benzene    as colorless powder. APCI-Mass m/Z 494 (M+NH₄).

EXAMPLE 1771-(β-D-glucopyranosyl)-3-(5-(3,4-difluorophenyl)-2-thienylmethyl)-4-methylbenzene

-   (1)    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-methylbenzene    obtained in Example 159-(1) and 3,4-difluorophenylboronic acid were    treated in a manner similar to Example 168-(1) to give    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(3,4-difluorophenyl)-2-thienylmethyl)-4-methylbenzene    as colorless crystals. APCI-Mass m/Z 648 (M+NH₄).-   (2) The above    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(3,4-difluorophenyl)-2-thienylmethyl)-4-methylbenzene    was treated in a manner similar to Example 106-(3) to give the    desired    1-(β-D-glucopyranosyl)-3-(5-(3,4-difluorophenyl)-2-thienylmethyl)-4-methylbenzene    as colorless powder. APCI-Mass m/Z 480 (M+NH₄).

EXAMPLE 1781-(β-D-glucopyranosyl)-4-chloro-3-(5-(3-difluoromethylphenyl)-2-thienylmethyl)benzene

-   (1)    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-chlorobenzene    71 obtained in Example 128—(4) and 3-formylphenylboronic acid were    treated in a manner similar to Example 168-(1) to give    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(3-formylphenyl)-2-thienylmethyl)benzene    as a colorless solid. APCI-Mass m/Z 660/662 (M+NH₄)-   (2) The above    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(3-formylphenyl)-2-thienylmethyl)benzene    was treated in a manner similar to Example 130—(2) to give    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(3-difluoromethylphenyl)-2-thienylmethyl)benzene    as colorless crystals. APCI-Mass m/Z 682/684 (M+NH₄).-   (3) The above    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(3-difluoromethylphenyl)-2-thienylmethyl)benzene    was treated in a manner similar to Example 120—(3) to give the    desired    1-(β-D-glucopyranosyl)-4-chloro-3-(5-(3-difluoromethylphenyl)-2-thienylmethyl)-benzene    as colorless powder. APCI-Mass m/Z 514/516 (M+NH₄)

EXAMPLE 1791-(β-D-glucopyranosyl)-4-chloro-3-(5-(4-difluoromethylphenyl)-2-thienylmethyl)benzene

-   (1)    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-chlorobenzene    71 obtained in Example 128-(4) and 4-formylphenylboronic acid were    treated in a manner similar to Example 168-(1) to give    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(4-formylphenyl)-2-thienylmethyl)benzene    as a colorless solid. APCI-Mass m/Z 660/662 (M+NH₄).-   (2) The above    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(4-formylphenyl)-2-thienylmethyl)benzene    was treated in a manner similar to Example 130—(2) to give    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(4-difluoromethylphenyl)-2-thienylmethyl)benzene    as colorless crystals. APCI-Mass m/Z 682/684 (M+NH₄)-   (3) The above    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(4-difluoromethylphenyl)-2-thienylmethyl)benzene    was treated in a manner similar to Example 120-(3) to give the    desired    1-(β-D-glucopyranosyl)-4-chloro-3-(5-(4-difluoromethylphenyl)-2-thienylmethyl)-benzene    as colorless powder. APCI-Mass m/Z 514/516 (M+NH₄).

EXAMPLE 1801-(β-D-glucopyranosyl)-4-chloro-3-(5-(4-difluoro-methyl-3-fluorophenyl)-2-thienylmethyl)benzene

-   (1)    1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-chlorobenzene    obtained in Example 128-(4) and 3-fluoro-4-formylphenylboronic acid    were treated in a manner similar to Example 168-(1) to give    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(3-fluoro-4-formylphenyl)-2-thienylmethyl)benzene    as colorless foam. APCI-Mass m/Z 678/680 (M+NH₄).-   (2)    1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(3-fluoro-4-formylphenyl)-2-thienylmethyl)-benzene    was treated in a manner similar to Example 178-(2) and-   (3) to give the desired    1-(β-D-glucopyranosyl)-4-chloro-3-(5-(4-difluoromethyl-3-fluorophenyl)-2-thienylmethyl)-benzene    as a colorless foam. APCI-Mass m/Z 532/534 (M+NH₄)

EXAMPLE 1811-(β-D-glucopyranosyl)-4-chloro-3-(5-(1H-tetrazol-5-yl)-2-thienylmethyl)benzene

-   (1)    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-chlorobenzene    obtained in Example 128-(4) and    (2-benzyloxymethyl-2H-tetrazol-5-yl)tri-n-butyltin (see Tetrahedron    Lett. (2000) 2805) were treated in a manner similar to Example    128-(5) to give    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(2-benzyloxymethyl-2H-tetrazol-5-yl)-2-thienylmethyl)-4-chlorobenzene    as colorless solid. APCI-Mass m/Z 727/729 (M+H).-   (2) A mixture of    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(2-benzyloxymethyl-2H-tetrazol-5-yl)-2-thienylmethyl)-4-chlorobenzene    (247 mg), 6M aqueous hydrochloric acid solution (2 ml) and methanol    (20 ml) was refluxed overnight. The solvent was evaporated under    reduced pressure and the residue was triturated with diethyl ether    to give the desired    1-(β-D-glucopyranosyl)-4-chloro-3-(5-(1H-tetrazol-5-yl)-2-thienylmethyl)benzene    (172 mg) as colorless powder. ESI-Mass m/Z 437/439 (M−H)

EXAMPLE 1821-(β-D-glucopyranosyl)-4-chloro-3-(5-(2-methyl-2H-tetrazol-5-yl)-2-thienylmethyl)benzene

1-(β-D-glucopyranosyl)-4-chloro-3-(5-(1H-tetrazol-5-yl)-2thienylmethyl)benzene(140 mg) obtained in Example 181 was dissolved in dimethylformamide (5ml) and added thereto were methyl iodide (100 μl) and potassiumcarbonate (220 mg). The mixture was stirred at room temperatureovernight. The reaction solution was poured into water and the mixturewas extracted with ethylacetate. The extract was washed with brine anddried over sodium sulfate, and the solvent was evaporated under reducedpressure to give the desired1-(β-D-glucopyranosyl)-4-chloro-3-(5-(2-methyl-2H-tetrazol-5-yl)-2-thienylmethyl)benzeneas colorless powder. APCI-Mass m/Z 470/472 (M+NH₄).

EXAMPLE 1831-(β-D-glucopyranosyl)-4-chloro-3-(5-(4-cyano-3-fluorophenyl)-2-thienylmethyl)benzene

-   (1)    1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(3-fluoro-4-formylphenyl)-2-thienylmethyl)benzene    (272 mg) obtained in Example 180-(1) was dissolved in    N-methyl-2-pyrrolidone (10 ml) and added thereto was hydroxylamine    hydrochloride (34 mg). The mixture was heated under stirring at    117° C. overnight. The reaction solution was cooled and diluted with    ethyl acetate and water. The organic layer was washed with water and    successively washed with brine. After drying over magnesium sulfate,    the solvent was evaporated under reduced pressure. The residue was    purified by silica gel column chromatography    (hexane:ethylacetate=3:1-2:1) to give    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(4-hydroxyimino-3-fluorophenyl)-2-thienylmethyl)benzene    (177 mg) as colorless caramel. APCI-Mass m/Z 693/695 (M+NH₄).-   (2) The above    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(4-hydroxyimino-3-fluorophenyl)-2-thienyl-methyl)    benzene (175 mg) was dissolved in chloroform (5 ml) and added    thereto was 1,1′-carbonyldiimidazole (46 mg). The mixture was    stirred at room temperature overnight. 1,1′-Carbonyl-diimidazole (92    mg) was further added thereto, and the mixture was stirred at 40° C.    for 6 hours. The reaction solution was cooled and diluted with ethyl    acetate and water. The organic layer was separated and successively    washed with brine. After drying over magnesium sulfate, the solvent    was evaporated under reduced pressure. The residue was purified by    silica gel column chromatography (hexane:ethyl acetate=2:1) to give    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(4-cyano-3-fluorophenyl)-2-thienylmethyl)benzene    (158 mg) as colorless caramel. APCI-Mass m/Z 675/677 (M+NH₄).-   (3) The above    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(4-cyano-3-fluorophenyl)-2-thienylmethyl)-benzene    was treated in a manner similar to Example 106-(3) to give desired    1-(β-D-glucopyranosyl)-4-chloro-3-(5-(4-cyano-3-fluorophenyl)-2-thienylmethyl)benzene    as pale yellow powder. APCI-Mass m/Z 507/509 (M+NH₄).

EXAMPLE 1841-(β-D-glucopyranosyl)-4-chloro-3-(1,3-dihydro-isoindol-2-ylmethyl)benzene

(In the above scheme, OTBDPS is a tert-butyldiphenylsilyloxy group, andthe other symbols are the same as defined above.)

-   (1) A mixed solution of    5-bromo-2-chloro-1-(tert-butyl-diphenylsilyloxymethyl)benzene 77    (10.83 g) and    2,3,4,6-tetrakis-O-trimethylsilyl-D-glucono-1,5-lactone 2 (see U.S.    Pat. No. 6,515,117) (13.2 g) in tetrahydrofuran (400 ml) was cooled    to −78° C. under argon atmosphere, and thereto was added dropwise    tert-butyl lithium (1.60 M pentane solution, 30.9 ml), and the    mixture was stirred at the same temperature for 30 minutes to give a    compound 78. Without isolating this compound, a solution of    methanesulfonic acid (6.12 ml) in methanol (200 ml) was added to the    reaction solution, and the reaction mixture was warmed to room    temperature, and stirred at the same temperature for 15 hours. Under    ice-cooling, to the mixture was added a saturated aqueous sodium    hydrogen carbonate solution, and the mixture was extracted with    ethyl acetate. The extract was washed with brine, and dried over    magnesium sulfate. The solvent was evaporated under reduced    pressure, and the residue was purified by silica gel column    chromatography (chloroform:methanol=93:7) to give a methyl ether    compound 79 (9.71 g) as colorless powder. APCI-Mass m/Z 590/592    (M+NH₄).-   (2) A solution of the above methyl ether compound 79 (3.46 g) in    dichloromethane (70 ml) was cooled to 0° C. under argon atmosphere,    and thereto were added dropwise successively triethylsilane    (2.89 ml) and boron trifluoride.diethyl ether complex (2.28 ml). The    mixture was stirred at the same temperature for 1 hour. Under    ice-cooling, a saturated aqueous sodium hydrogen carbonate solution    was added, and the mixture was extracted with ethyl acetate. The    extract was washed with brine and dried over magnesium sulfate, and    the solvent was evaporated under reduced pressure. The residue was    purified by silica gel column chromatography    (chloroform:methanol=100:0-94:4) to give    1-(β-D-glucopyranosyl)-4-chloro-3-(tert-butyldiphenylsilyloxymethyl)benzene    80 (2.52 g) as colorless powder. APCI-Mass m/Z 560/562 (M+NH₄).-   (3) The above compound 80 (4.12 g) was treated in a manner similar    to Example 106-(1) to give the compound 81 (5.44 g). APCI-Mass m/Z    728/730 (M+NH₄).-   (4) A mixed solution of the above compound 81 (5.44 g), acetic acid    (1.29 ml) in tetrahydrofuran (60 ml) was cooled to 0° C. under argon    atmosphere, and thereto was added tetrabutyl ammonium fluoride (1.0    M tetrahydrofuran solution, 8.43 ml). The mixture was stirred at the    same temperature for 30 minutes, and then further stirred at room    temperature for 15 hours. The mixture was diluted with ethyl acetate    and washed successively with 0.4 M aqueous hydrochloric acid    solution, a saturated aqueous sodium hydrogen carbonate solution and    brine. The mixture was dried over magnesium sulfate, and the solvent    was evaporated under reduced pressure. The residue was purified by    silica gel column chromatography (hexane:ethyl acetate=4:1-1:1) to    give the compound 82 (2.97 g) as a colorless solid. APCI-Mass m/Z    490/492 (M+NH₄).-   (5) A solution of the above compound 82 (1.60 g) in dichloromethane    (50 ml) was cooled to 0° C. under argon atmosphere, and thereto was    added Dess-Martin periodinane (1.58 g). The mixture was warmed to    room temperature and stirred at the same temperature for 3 hours.    The mixture was diluted with ethyl acetate, and insoluble materials    were filtered off. The filtrate was washed successively with a    saturated aqueous sodium hydrogen carbonate solution and brine, and    dried over magnesium sulfate. The solvent was evaporated under    reduced pressure, and the residue was purified by silica gel column    chromatography (hexane:ethyl acetate=3:1-1:1) to give    5-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-2-chloro-benzaldehyde    83 (1.35 g) as colorless crystals. APCI-Mass m/Z 488/490 (M+NH₄).-   (6) To a mixed solution of the above    5-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-2-chlorobenzaldehyde    83 (325 mg), 2,3-dihydro-1H-isoindole (98 mg), acetic acid (82 mg)    in 1,2-dichloroethane (5 ml) was added sodium triacetoxyborohydride    (219 mg). The mixture was stirred at room temperature for 3 hours,    and cooled to 0° C. A saturated aqueous sodium hydrogen carbonate    solution was added thereto to basify the reaction mixture. The    mixture was extracted with ethyl acetate, and the extract was washed    with brine, and dried over magnesium sulfate. The solvent was    evaporated under reduced pressure, and the residue was purified by    silica gel column chromatography (hexane:ethyl acetate=1:0-1:1) to    give    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(1,3-dihydro-isoindol-2-ylmethyl)benzene    84 (234 mg) as a colorless solid. APCI-Mass m/Z 574/576 (M+H).-   (7) The above    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(1,3-dihydro-isoindol-2-yl-methyl)benzene    84 was treated in a manner similar to Example 106-(3) to give the    desired    1-(β-D-glucopyranosyl)-4-chloro-3-(1,3-dihydro-isoindol-2-ylmethyl)benzene    85 as colorless powder. APCI-Mass m/Z 406/408 (M+H).

EXAMPLE 1851-(β-D-glucopyranosyl)-4-methyl-3-(5-(3-cyano-4-fluorophenyl)-2-thienylmethyl)benzene

1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-methylbenzeneobtained in Example 159—(1) and 4-fluoro-3-formylphenylboronic acid wereused and treated in a manner similar to Example 177-(1) and Example 183to give the title compound as colorless powder. APCI-Mass m/z 487(M+NH₄).

EXAMPLE 1861-(β-D-glucopyranosyl)-3-(5-(2-cyano-5-pyridyl)-2-thienylmethyl)-4-methylbenzene

-   (1)    1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-methylbenzene    (597 mg) obtained in Example 159—(1) was dissolved in    N-methyl-2-pyrrolidone (10 ml) and added thereto were    tri-n-butyl(2-cyano-5-pyridyl)tin (590 mg),    dichlorobis(triphenylphosphine)palladium(II) (70 mg) and    copper(I)iodide (19 mg). The mixture was heated under stirring at    100° C. for 4 hours. The reaction solution was cooled and diluted    with ethyl acetate and water. The organic layer was washed with    water and successively washed with brine. After drying over    magnesium sulfate, the solvent was evaporated under reduced    pressure. The residue was purified by silica gel column    chromatography (hexane:ethyl acetate=2:1) to give    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(2-cyano-5-pyridyl)-2-thienylmethyl)-4-methylbenzene    (351 mg) as colorless powder. APCI-Mass m/Z 621 (M+H).-   (2) The above    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(2-cyano-5-pyridyl)-2-thienylmethyl)-4-methylbenzene    (62 mg) was dissolved in a mixture of tert-butanol (3    ml)-tetrahydrofuran (3 ml) and added thereto was sodium    tert-butoxide (48 mg). The mixture was stirred at room temperature    for 3.5 hours. Sodium tert-butoxide (19 mg) was further added    thereto, and the mixture was stirred at room temperature for 1 hour.    To the mixture was added a saturated aqueous ammonium chloride    solution at 0° C., and the mixture was extracted with ethyl acetate    twice. The extract was washed with brine, dried over magnesium    sulfate, and the solvent was evaporated under reduced pressure. The    residue was purified by silica gel column chromatography    (chloroform:methanol=19:1) to give the desired    1-(β-D-glucopyranosyl)-3-(5-(2-cyano-5-pyridyl)-2-thienylmethyl)-4-methylbenzene    (23 mg) as colorless powder. APCI-Mass m/Z 470 (M+NH₄)

EXAMPLE 1871-(β-D-glucopyranosyl)-4-chloro-3-(5-(2-cyano-5-pyridyl)-2-thienylmethyl)benzene

-   (1)    1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-chlorobenzene    obtained in Example 128-(4) was treated in a manner similar to    Example 186-(1) to give    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(2-cyano-5-pyridyl)-2-thienylmethyl)benzene    as colorless powder. APCI-Mass m/Z 641/643 (M+H).-   (2)    1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(2-cyano-5-pyridyl)-2-thienylmethyl)benzene    was treated in a manner similar to Example 186-(2) to give the    desired    1-(β-D-glucopyranosyl)-4-chloro-3-(5-(2-cyano-5-pyridyl)-2-thienylmethyl)benzene    as pale yellow powder. APCI-Mass m/Z 490/492 (M+NH₄).

EXAMPLE 1881-(β-D-glucopyranosyl)-3-(5-(2-carbamoyl-5-pyridyl)-2-thienylmethyl)-4-chlorobenzene

-   (1)    1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(2-cyano-5-pyridyl)-2-thienylmethyl)benzene    obtained in Example 187-(1) was treated in a manner similar to    Example 106—(3) to give the mixture of    1-(β-D-glucopyranosyl)-4-chloro-3-(5-(2-cyano-5-pyridyl)-2-thienylmethyl)benzene    and    1-(β-D-glucopyranosyl)-4-chloro-3-(5-(2-methoxyimidoyl-5-pyridyl)-2-thienylmethyl)benzene.    This mixture was dissolved in methanol, and sodium methoxide (28%    methanol solution, 1 drop) was added thereto, and the mixture was    stirred at 60° C. for 6 hours. The reaction solution was cooled and    the solvent was evaporated under reduced pressure to give pure    1-(β-D-glucopyranosyl)-4-chloro-3-(5-(2-methoxyimidoyl-5-pyridyl)-2-thienylmethyl)benzene.    APCI-Mass m/Z 505/507 (M+H).-   (2) The above    1-(β-D-glucopyranosyl)-4-chloro-3-(5-(2-methoxyimidoyl-5-pyridyl)-2-thienylmethyl)benzene    was suspended in tetrahydrofuran, and sodium hydride (60% mineral    oil suspension, 2 equivalent) was added thereto, and the mixture was    stirred under reflux for 3 hours. The reaction solution was cooled    and to the mixture was added a saturated aqueous ammonium chloride    solution at 0° C., and the mixture was extracted with a mixture of    ethyl acetate and tetrahydrofuran. The extract was washed with    brine, dried over magnesium sulfate, and the solvent was evaporated    under reduced pressure. The residue was purified by silica gel    column chromatography (chloroform:methanol=9:1-5:1) to give the    desired    1-(β-D-glucopyranosyl)-3-(5-(2-carbamoyl-5-pyridyl)-2-thienylmethyl)-4-chlorobenzene    as pale yellow powder. APCI-Mass m/Z 491/493 (M+H).

EXAMPLE 1891-(β-D-glucopyranosyl)-4-fluoro-3-(5-(3-cyanophenyl)-2-thienylmethyl)benzene

-   (1) 5-bromo-2-fluorobenzaldehyde and 2-chlorothiophene were used and    treated in a manner similar to Example 4 and Example 106-(1) to give    1-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyl)-3-(5-chloro-2-thienylmethyl)-4-fluorobenzene    as colorless crystals. APCI-Mass m/z 574/576 (M+NH₄). mp 130-131° C.-   (2) The above compound was treated in a manner similar to EXAMPLE    158-(1) to give    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(2-thienylmethyl)-4-fluorobenzene    as colorless crystals. APCI-Mass m/z 540 (M+NH₄). mp 119-121° C.-   (3) The above compound was treated in a manner similar to Example    159—(1) to give    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-fluorobenzene    as colorless crystals. APCI-Mass m/z 618/620 (M+NH₄). mp 127-129° C.-   (4) The above compound and 3-cyanophenylboronic acid were used and    treated in a manner similar to Example 168 to give the title    compound as colorless powder. APCI-Mass m/z 473 (M+NH₄).

EXAMPLE 1901-(β-D-glucopyranosyl)-4-fluoro-3-(5-(2-thiazolyl)-2-thienylmethyl)benzene

1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-fluorobenzeneobtained in Example 189-(3) and tri-n-butyl(2-thiazolyl)tin were usedand treated in a manner similar to Example 128 to give the titlecompound as colorless crystals. APCI-Mass m/z 438 (M+NH₄). mp 161.5-162°C.

EXAMPLE 1911-(β-D-glucopyranosyl)-4-chloro-3-(5-(4-ethoxycarbonylphenyl)-2-thienylmethyl)benzene

-   (1)    1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-chlorobenzene    obtained in Example 128—(4) and 4-cyanophenylboronic acid were    treated in a manner similar to Example 168-(1) to give    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(4-cyanophenyl)-2-thienylmethyl)benzene    as colorless powder. APCI-Mass m/Z 657/659 (M+NH₄).-   (2) The above    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(4-cyanophenyl)-2-thienylmethyl)benzene    (128 mg) was suspended in ethanol (2 ml) and added thereto was a    concentrated hydrochloric acid aqueous solution (1 ml). The mixture    was heated reflux for 8.5 hours. The reaction solution was cooled    and diluted with ethyl acetate and water. The organic layer was    washed with water and successively washed with brine. After drying    over magnesium sulfate, the solvent was evaporated under reduced    pressure. The residue was purified by silica gel column    chromatography (chloroform:methanol=9:1) to give the desired    1-(β-D-glucopyranosyl)-4-chloro-3-(5-(4-ethoxycarbonylphenyl)-2-thienylmethyl)benzene    (39 mg) as pale yellow foam. APCI-Mass m/Z 536/538 (M+NH₄).

EXAMPLE 1921-(β-D-glucopyranosyl)-3-(5-(4-carboxyphenyl)-2-thienylmethyl)-4-chlorobenzene

1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(4-cyanophenyl)-2-thienylmethyl)benzene(128 mg) obtained in Example 191—(1) was dissolved in acetic acid (2 ml)and added thereto was a concentrated hydrochloric acid aqueous solution(2 ml). The mixture was refluxed for 6.5 hours. To the mixture was addeda 10% aqueous sodium hydroxide solution at 0° C., and the mixture waswashed with ethyl acetate. The aqueous layer was acidified by addingconcentrated hydrochloric acid, and extracted with a mixture of ethylacetate and tetrahydrofuran. The extract was dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theresidue was purified by washing with a mixture of ethyl acetate anddiethyl ether to give the desired1-(β-D-glucopyranosyl)-3-(5-(4-carboxyphenyl)-2-thienylmethyl)-4-chlorobenzene(49 mg) as pale brown powder. ESI-Mass m/Z 489/491 (M−H).

EXAMPLE 1931-(β-D-glucopyranosyl)-3-(5-(4-carbamoylphenyl)-2-thienylmethyl)-4-chlorobenzene

1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(4-cyanophenyl)-2-thienylmethyl)benzene(282 mg) obtained in Example 191-(1) was suspended in ethanol (5 ml) andadded thereto was a 6N aqueous sodium hydroxide solution (0.37 ml). Themixture was stirred at room temperature for 10 minutes. To the mixturewas added a 30% aqueous hydrogen peroxide solution (0.2 ml), and themixture was stirred at room temperature for 1.5 hours and at 45° C. for3 hours. To the mixture was added water (20 ml) and the mixture wascooled. The powder was collected by filtration and washed with diethylether and dried to give the desired1-(β-D-glucopyranosyl)-3-(5-(4-carbamoyl-phenyl)-2-thienylmethyl)-4-chlorobenzene(176 mg) as colorless powder. APCI-Mass m/Z 507/509 (M+NH₄).

EXAMPLE 1941-(β-D-glucopyranosyl)-4-chloro-3-(5-(5-fluoropyridin-2-yl)-2-thienylmethyl)benzene

In the above scheme, the symbols are defined as above.

-   (1) The    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)₄-chlorobenzene    71 (750 mg) obtained in Example 128-(4) was dissolved in a mixture    of methanol (8 ml)-tetrahydrofuran (8 ml), and sodium methoxide (28%    methanol solution, 1 drop) was added thereto, and the mixture was    stirred at room temperature for 2 hours. The solvent was evaporated    under reduced pressure. The residue was dissolved in dichloromethane    (20 ml), and thereto were added pyridine (0.69 ml) and    4-dimethylaminopyridine (15 mg). The mixture was cooled to 0° C.,    and thereto was added trimethylsilyl trifluoromethanesulfonate (1.54    ml). The mixture was stirred at room temperature for 3 days. To the    mixture was added water, and the mixture was extracted with diethyl    ether. The extract was washed with successively with water, a    saturated aqueous ammonium chloride solution and brine, and dried    over sodium sulfate. The solvent was evaporated under reduced    pressure to give the compound 86 (900 mg) as colorless oil.-   (2) A mixed solution of the above compound 86 (900 mg),    triisopropoxyborane (252 mg) in tetrahydrofuran (22 ml) was cooled    to −78° C. under argon atmosphere. Thereto was added dropwise    tert-butyl lithium (1.46 M pentane solution, 0.9 ml), and the    mixture was stirred at the same temperature for 1 hour. The mixture    was warmed to room temperature, and thereto was added pinacol (2.24    g). The mixture was stirred at the same temperature overnight. The    mixture was diluted with ethyl acetate, and washed successively with    water and brine. The solvent was evaporated under reduced pressure    to give the compound 87, which was used in the subsequent reaction    without further purification.-   (3) The whole amount of the above compound 87 was dissolved in    dimethoxyethane (20 ml), and thereto were added    2-bromo-5-fluoropyridine (460 mg),    tetrakis(triphenylphosphine)palladium(0) (150 mg) and cesium    fluoride (1.4 g). The mixture was stirred at 80° C. for 3 hours. The    mixture was cooled to room temperature, acidified with 2 M aqueous    hydrochloric acid solution, and stirred at the same temperature    overnight. Under ice-cooling, the reaction mixture was poured into a    saturated aqueous sodium hydrogen carbonate solution and the mixture    was extracted with ethyl acetate. The extract was washed with brine    and dried over sodium sulfate, and the solvent was evaporated under    reduced pressure. The residue was passed through silica gel column    chromatography (chloroform:methanol=100:0-88:12) to give crude oil,    which was dissolved in dichloromethane (20 ml). To the mixture were    added acetic anhydride (0.71 ml), pyridine (0.61 ml), and    4-dimethylaminopyridine (13 mg), and the mixture was stirred at room    temperature for 1 hour. Then, dichloromethane was evaporated under    reduced pressure, and the residue was dissolved in ethyl acetate.    The mixture was washed successively with 2 M aqueous hydrochloric    acid solution, a saturated aqueous sodium hydrogen carbonate    solution, and brine, dried over sodium sulfate. The solvent was    evaporated under reduced pressure, and the residue was purified by    silica gel column chromatography (hexane:ethyl acetate=1:0-3:2) to    give    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(5-fluoropyridin-2-yl)-2-thienylmethyl)benzene    88 (218 mg) as a colorless solid. APCI-Mass m/Z 634/636 (M+H)-   (4) The above    1-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyl)-4-chloro-3-(5-(5-fluoropyridin-2-yl)-2-thienyl-methyl)benzene    88 was treated in a manner similar to Example 106-(3) to give the    desired    1-(β-D-glucopyranosyl)-4-chloro-3-(5-(5-fluoropyridin-2-yl)-2-thienylmethyl)benzene    89 as a colorless solid. APCI-Mass m/Z 466/468 (M+H).

EXAMPLE 1951-(β-D-glucopyranosyl)-3-(benzo[b]thiophen-2-ylmethyl)-indole

In the above scheme, the symbols are defined as above.

-   (1) 1-(β-D-glucopyranosyl)indole 90 (see Eur. J. Med. Chem. (2004)    39, 453-458) was treated in a manner similar to Example 106-(1) to    give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indole 91 as    colorless crystals. APCI-Mass m/Z 465 (M+NH₄).-   (2) Benzo[b]thiophene-2-carboxylic acid (598 mg) was suspended in    dichloromethane (10 ml). Added thereto were oxalyl chloride    (0.39 ml) and N,N-dimethylformamide (one drop), and the mixture was    stirred at room temperature overnight. The solvent was evaporated    under reduced pressure to give a corresponding acid chloride, which    was dissolved in dichloroethane (30 ml). To the solution was added    1-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyl)indole 91 (1 g)    obtained above, and the mixture was cooled to 0° C. Added gradually    thereto was aluminum chloride (2.09 g), and subsequently, the    mixture was stirred at the same temperature for 30 minutes. The    reaction mixture was poured into ice-cold water, and the mixture was    extracted with chloroform. The extract was washed successively with    water, a saturated aqueous sodium hydrogen carbonate solution and    brine, dried over sodium sulfate, and the solvent was evaporated    under reduced pressure. The residue was purified by silica gel    column chromatography (hexane:ethyl acetate=9:1-5:4) to give    Benzo[b]thiophen-2-yl(1-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyl)-indol-3-yl)    ketone 92 (570 mg) as colorless crystals. APCI-Mass m/Z 608 (M+H).-   (3) The above    Benzo[b]thiophen-2-yl(1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-indol-3-yl)    ketone 92 (440 mg) was dissolved in tetrahydrofuran (6 ml) and    ethanol (3 ml). To the solution was added sodium borohydride (137    mg), and the mixture was stirred at room temperature for 60 minutes.    The reaction mixture was quenched with cold aqueous HCl solution    (0.5 N), and extracted with ethyl acetate. The extract was washed    successively with water, a saturated aqueous sodium hydrogen    carbonate solution and brine, and dried over sodium sulfate. The    solvent was evaporated under reduced pressure. The resultant residue    was dissolved in dichloromethane (8 ml) and acetonitrile (4 ml), and    the mixture was cooled to 0° C. under argon atmosphere. To the    mixture were added triethylsilane (0.58 ml) and boron    trifluoride.diethyl ether complex (0.46 ml). After 30 minutes, the    mixture was basified with a saturated aqueous sodium hydrogen    carbonate solution, and the organic layer was collected, dried over    magnesium sulfate, and the solvent was evaporated under reduced    pressure. The resultant residue was dissolved in chloroform (20 ml),    and to the mixture were added acetic anhydride (0.16 ml),    triethylamine (0.2 ml), and 4-dimethylaminopyridine (15 mg), and the    mixture was stirred at room temperature for 30 minutes. Then, the    solution was washed successively with 10% aqueous hydrochloric acid    solution, water, a saturated aqueous sodium hydrogen carbonate    solution, and brine, and dried over magnesium sulfate. The solvent    was evaporated under reduced pressure, and the resultant residue was    purified by silica gel column chromatography (hexane:ethyl    acetate=8:2-6:4) to give    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(benzo-[b]thiophen-2-ylmethyl)indole    93 (290 mg). APCI-Mass m/Z 611 (M+NH₄).-   (4) The above    1-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyl)-3-(benzo[b]thiophen-2-ylmethyl)indole    93 (336 mg) was treated in a manner similar to Example 106-(3) to    give the desired    1-(β-D-glucopyranosyl)-3-(benzo[b]thiophen-2-yl-methyl) indole 94    (208 mg) as a colorless powder. APCI-Mass m/Z 443 (M+NH₄)

EXAMPLE 1961-(β-D-glucopyranosyl)-3-(5-(3-cyanophenyl)-2-thienyl-methyl)-4-fluoronaphthalene

-   (1) The    1-(β-D-glucopyranosyl)-3-(5-chloro-2-thienyl-methyl)-4-fluoronaphthalene    obtained in Example 137 was treated in a manner similar to Example    106-(1) to give    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-chloro-2-thienylmethyl)-4-fluoronaphthalene.    APCI-Mass m/Z 624/626 (M+NH₄).-   (2) The above    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-chloro-2-thienylmethyl)-4-fluoronaphthalene    was treated in a manner similar to Example 158-(1) to give    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(2-thienyl-methyl)-4-fluoronaphthalene.    APCI-Mass m/Z 590 (M+NH₄).-   (3) The above    1-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyl)-3-(2-thienylmethyl)-4-fluoronaphthalene    was treated in a manner similar to Example 159-(1) to give    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-fluoronaphthalene.    APCI-Mass m/Z 668/670 (M+NH₄).-   (4) The above    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-fluoronaphthalene    and 3-cyanophenylboronic acid were treated in a manner similar to    Example 168 to give    1-(β-D-glucopyranosyl)-3-(5-(3-cyanophenyl)-2-thienyl-methyl)-4-fluoronaphthalene.    APCI-Mass m/Z 523 (M+NH₄).

EXAMPLE 1971-(β-D-glucopyranosyl)-3-(5-(4-aminophenyl)-2-thienyl-methyl)-4-chlorobenzene

-   (1)    1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-chlorobenzene    obtained in EXAMPLE 128-(4) and    4-(4,4,5,5-tetramethyl-1,3-dioxaborolan-2-yl)aniline were treated in    a manner similar to Example 168-(1) to give    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(4-aminophenyl)-2-thienylmethyl)-4-chlorobenzene    as pale yellow powder. APCI-Mass m/Z 630/632 (M+H).-   (2) The above    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(4-aminophenyl)-2-thienylmethyl)-4-chlorobenzene    was treated in a manner similar to Example 106-(3) to give the    desired    1-(β-D-glucopyranosyl)-3-(5-(4-aminophenyl)-2-thienylmethyl)-4-chlorobenzene    as pale yellow foam. APCI-Mass m/Z 479/481 (M+NH₄).

EXAMPLE 1981-(β-D-glucopyranosyl)-4-chloro-3-(5-(4-methylcarbamoyl-phenyl)-2-thienylmethyl)benzene

-   (1)    1-(β-D-Glucopyranosyl)-3-(5-(4-carboxyphenyl)-2-thienylmethyl)-4-chlorobenzene    (637 mg) obtained in Example 192 was dissolved in a mixture of    dichloromethane (10 ml)-tetrahydrofuran (5 ml) and added thereto    were acetic anhydride (1.22 ml), pyridine (1.05 ml) and    4-dimethylaminopyridine (32 mg). The mixture was stirred at room    temperature overnight. The solvents were evaporated under reduced    pressure and the residue was dissolved in ethyl acetate. The organic    layer was washed with 2N hydrochloric acid aqueous solution and    successively washed with brine. After drying over magnesium sulfate,    the solvent was evaporated under reduced pressure. The residue was    purified by silica gel column chromatography    (chloroform:methanol=100:1-50:1) to give    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(4-carboxyphenyl)-2-thienylmethyl)-4-chlorobenzene    (687 mg) as pale yellow powder. ESI-Mass m/Z 657/659 (M−H).-   (2) The above    1-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyl)-3-(5-(4-carboxyphenyl)-2-thienylmethyl)-4-chloro    benzene (198 mg) was dissolved in dichloromethane (5 ml) and added    thereto were oxalyl chloride (1 ml) and N,N-dimethylformamide (one    drop), and the mixture was stirred at room temperature for 3.5    hours. The solvent was evaporated under reduced pressure to give a    corresponding acid chloride, which was suspended in tetrahydrofuran    (4 ml), without further purification. To the suspension was added a    2.0 M solution of methylamine in tetrahydrofuran (1.5 ml), and the    mixture was stirred at room temperature for 2 hours. The solvent was    evaporated under reduced pressure, and the residue was purified by    silica gel column chromatography (chloroform:methanol=100:1) to give    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(4-methylcarbamoylphenyl)-2-thienylmethyl)-benzene    (218 mg) as pale yellow powder. APCI-Mass m/Z 689/691 (M+NH₄).-   (3) The above    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(4-methylcarbamoylphenyl)-2-thienylmethyl)-benzene    was treated in a manner similar to Example 106-(3) to give the    desired    1-(β-D-glucopyranosyl)-4-chloro-3-(5-(4-methylcarbamoylphenyl)-2-thienylmethyl)benzene    as colorless powder. APCI-Mass m/Z 521/523 (M+NH₄).

EXAMPLE 1991-(β-D-glucopyranosyl)-4-chloro-3-(5-(4-methylsulfonyl-aminophenyl)-2-thienylmethyl)benzene

-   (1)    1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(4-aminophenyl)-2-thienylmethyl)-4-chlorobenzene    (126 mg) obtained in Example 197-(1) was dissolved in    dichloromethane (3 ml) and added thereto were methanesulfonyl    chloride (48 mg) and pyridine (48 mg). The mixture was stirred at    room temperature for 3.5 hours. To the mixture was added 2N    hydrochloric acid aqueous solution at 0° C. and extracted with ethyl    acetate. The organic layer was washed with water, aqueous sodium    hydrogen carbonate solution and successively washed with brine.    After drying over magnesium sulfate, the solvent was evaporated    under reduced pressure. The residue was purified by silica gel    column chromatography (hexane:ethyl acetate=1:1-1:2) to give    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(4-methylsulfonylamino-phenyl)-2-thienylmethyl)benzene    (154 mg) as yellow caramel. ESI-Mass m/Z 706/708 (M−H).-   (2) The above    1-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyl)-4-chloro-3-(5-(4-methylsulfonylaminophenyl)-2-thienylmethyl)benzene    was treated in a manner similar to Example 106—(3) to give the    desired    1-(β-D-glucopyranosyl)-4-chloro-3-(5-(4-methylsulfonylaminophenyl)-2-thienyl-methyl)benzene    as yellow foam. ESI-Mass m/Z 538/540 (M−H).

EXAMPLE 200 1-(β-D-glucopyranosyl)-3-(5-(4-acetylaminophenyl)-2-thienylmethyl)-4-chlorobenzene

1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(4-aminophenyl)-2-thienylmethyl)-4-chlorobenzene(126 mg) obtained in Example 197-(1) was treated in a manner similar toExample 106—(1) and (3) to give the target compound as colorless powder.APCI-Mass m/Z 521/523 (M+NH₄).

The compounds shown in Table 5 below were prepared in a manner similarto one of the above Examples from the corresponding starting materials.The numbers shown in a column of “preparation method” in the Tableindicates the Example number, according to which the preparation wascarried out.

TABLE 5

Examples

Preparation Method APCI-Mass (m/Z) 201

177 480 (M + NH₄) 202

168 500/502 (M + NH₄) 203

177 496/498 (M + NH₄) 204

128 454/456 (M + H) 205

168 500/502 (M + NH₄) 206

168 516/518 (M + NH₄) 207

128 454/456 (M + H) 208

164 458 (M + H) 209

177 458 (M + H) 210

164 434 (M + H) 211

177 450 (M + NH₄) 212

177 488 (M + NH₄) 213

1 482/484 (M + NH₄) 214

2 437/439 (M + H) 215

183 507/509 (M + NH₄) 216

168 466/468 (M + H) 217

177 446 (M + H) 218

164 434 (M + H) 219

185 487 (M + NH₄) 220

176 512 (M + NH₄) 221

168 530/532 (M + NH₄) 222

177 510 (M + NH₄) 223

2 504/506 (M + NH₄) 224

2 484 (M + NH₄) 225

186 470 (M + NH₄) 226

187 490/492 (M + NH₄) 227

2 417 (M + H) 228

1 462 (M + NH₄) 229

1 448 (M + NH₄) 230

1 480 (M + NH₄) 231

1 462 (M + NH₄) 232

177 488 (M + NH₄) 233

1 500/502 (M + NH₄) 234

168 494/496 (M + NH₄) 235

1 480 (M + NH₄) 236

168 530/532 (M + NH₄) 237

177 510 (M + NH₄) 238

1 448 (M + NH₄) 239

184 420/422 (M + H) 240

128 438/440 (M + H) 241

164 418 (M + H) 242

128 469/471 (M + NH₄) 243

1 434/436 (M + H) 244

128 468/470 (M + H) 245

189 473 (M + NH₄) 246

164 449 (M + NH₄) 247

168 483/485 (M + NH₄) 248

189 467 (M + NH₄) 249

168 492/494 (M + NH₄) 250

1 468/470 (M + NH₄) 251

168 499/501 (M + NH₄) 252

128 468/470 (M + H) 253

168 462/464 (M + H) 254

193 507/509 (M + NH₄) 255

196 517 (M + NH₄) 256

1 472/474 (M + H) 257

168 509/511 (M + NH₄) 258

168 490/492 (M + H) 259

198 535/537 (M + NH₄) 260

198 549/551 (M + NH₄)

The compounds shown in Table 6 below were prepared in a manner similarto Example 195 from the corresponding starting materials.

TABLE 6

Examples

APCI-Mass (m/Z) 261

449/451 (M + NH₄) 262

432/434 (M + H) 263

449/451 (M + NH₄)

EXAMPLE 2641-(β-D-glucopyranosyl)-4-chloro-3-(5-(4-hydroxymethyl-phenyl)-2-thienylmethyl)benzene

1-(β-D-Glucopyranosyl)-4-chloro-3-(5-(4-formylphenyl)-2-thienylmethyl)benzene(84 mg) obtained in Example 249 was dissolved in a mixture of ethanol (2ml)-tetrahydrofuran (2 ml) and added thereto was sodium borohydride (7mg). The mixture was stirred at room temperature for 1 hour. The mixturewas quenched by 2N hydrochloric acid aqueous solution (3 drops) at 0°C., and the solvents were evaporated under reduced pressure. The residuewas purified by silica gel column chromatography(chloroform:methanol=9:1) to give the desired1-(β-D-glucopyranosyl)-4-chloro-3-(5-(4-hydroxymethylphenyl)-2-thienylmethyl)benzene(82 mg) as colorless foam. APCI-Mass m/Z 494/496 (M+NH₄).

EXAMPLE 2651-(β-D-glucopyranosyl)-3-(5-phenyl-2-thienylmethyl)-4-methoxynaphthalene

-   (1)    1-(β-D-Glucopyranosyl)-3-(5-chloro-2-thienyl-methyl)-4-methoxynaphthalene    obtained in Example 250 was treated in a manner similar to Example    106-(1) to give    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-chloro-2-thienylmethyl)-4-methoxynaphthalene.    APCI-Mass m/Z 636/638 (M+NH₄).-   (2) The above    1-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyl)-3-(5chloro-2-thienylmethyl)-4-methoxynaphthalene    was treated in a manner similar to Example 158-(1) to give    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(2-thienyl-methyl)-4-methoxynaphthalene.    APCI-Mass m/Z 602 (M+NH₄).-   (3) The above    1-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyl)-3-(2-thienylmethyl)-4-methoxynaphthalene    was treated in a manner similar to Example 159-(1) to give    1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-methoxynaphthalene.    APCI-Mass m/Z 680/682 (M+NH₄).-   (4) The above    1-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyl)-3-(5-bromo-2-thienylmethyl)-4-methoxynaphthalene    and phenylboronic acid were treated in a manner similar to Example    168 to give the desired    1-(β-D-glucopyranosyl)-3-(5-phenyl-2-thienyl-methyl)-4-methoxynaphthalene.    APCI-Mass m/Z 510 (M+NH₄).

EXAMPLE 2661-(β-D-glucopyranosyl)-3-(5-(2-pyrimidinyl)-2-thienylmethyl)-4-methoxynaphthalene

1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-methoxylnaphthaleneobtained in Example 265-(3) and 2-tributylstannylpyrimidine were treatedin a manner similar to Example 128-(5) and (6) to give1-(β-D-glucopyranosyl)-3-(5-(2-pyrimidinyl)-2-thienyl-methyl)-4-methoxylnaphthalene.APCI-Mass m/Z 495 (M+H).

The compounds shown in Table 7 below were prepared in a manner similarto Example 265 from the corresponding starting materials.

TABLE 7

Examples

APCI-Mass (m/Z) 267

535 (M + NH₄) 268

529 (M + NH₄)

REFERENCE EXAMPLE 1 3-Bromo-1-(5-ethyl-2-thienylmethyl)benzene

-   (1) A solution of 1,3-dibromobenzene (3.7 g) in tetrahydro-furan    (25 ml) was cooled to −78° C. under argon atmosphere, and thereto    was added dropwise n-butyl lithium (2.44 M hexane solution, 5.55    ml). The reaction mixture was stirred at the same temperature for 10    minutes, and thereto was added dropwise a solution of    5-ethyl-2-thiophenecarboxaldehyde (2.0 g) in tetrahydrofuran (10    ml). The mixture was stirred at the same temperature for 30 minutes,    and thereto was added a saturated ammonium chloride solution, and    the reaction mixture was warmed to room temperature. The mixture was    extracted with ethyl acetate, and the extract was dried over    magnesium sulfate, and the solvent was evaporated under reduced    pressure. The residue was purified by silica gel column    chromatography (hexane:ethyl acetate=97:3-85:15) to give    3-bromophenyl-5-ethyl-2-thienylmethanol (2.97 g) as a pale yellow    syrup. APCI-Mass m/Z 279/281 (M+H—H₂O).-   (2) The above 3-bromophenyl-5-ethyl-2-thienylmethanol (2.90 g) was    dissolved in dichloromethane (38 ml), and the mixture was cooled to    −78° C. under argon atmosphere. To the mixture were added    triethylsilane (6.18 ml) and boron trifluoride.diethyl ether complex    (2.45 ml), and the mixture was gradually warmed to room temperature    over a period of one hour. The mixture was basified with a saturated    aqueous sodium hydrogen carbonate solution, and the dichloromethane    layer was collected, dried over magnesium sulfate, and the solvent    was evaporated under reduced pressure. The residue was purified by    silica gel column chromatography (hexane) to give the desired    3-bromo-(5-ethyl-2-thienylmethyl)benzene (2.57 g) as a colorless    syrup. APCI-Mass m/Z 281/283 (M+H)

REFERENCE EXAMPLE 2 5-Bromo-1-(4-ethylphenylmethyl)-1H-pyridin-2-one

5-Bromo-1H-pyridin-2-one (1.04 g) and 4-ethylbenzyl bromide (1.43 g)were dissolved in N,N-dimethylformamide (15 ml), and thereto was addedpotassium carbonate (1.66 g). The mixture was stirred at roomtemperature overnight, diluted with ethyl acetate, and washedsuccessively with water and brine. The extract was dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane:ethylacetate=10:1-3:1) to give5-bromo-1-(4-ethylphenylmethyl)-1H-pyridin-2-one (1.58 g) as colorlesscrystals. APCI-Mass m/Z 292/294 (M+H).

REFERENCE EXAMPLE 3

In the above scheme, the symbols are as defined above.

-   (1) A solution of silylated glucal 75 (see Parker et al., Org. Lett.    2000, 2, 497-499) (7.00 g) in tetrahydrofuran (70 ml) was cooled to    −78° C. under argon atmosphere. Thereto was added dropwise t-butyl    lithium (1.45 M pentane solution, 49.0 ml) over a period of 10    minutes. The mixture was stirred at the same temperature for 15    minutes, and then warmed to room temperature, and further stirred    for 30 minutes. The mixture was cooled again to −78° C., and thereto    was added trimethyl borate (8.90 ml) in one portion. After 15    minutes, the reaction solution was warmed to room temperature over a    period of one hour, and thereto was added water (100 ml) at 0° C.    The mixture was stirred for 30 minutes, and extracted twice with    diethyl ether. The extract was washed with water, and then washed    with brine. The resultant was dried over magnesium sulfate, and the    solvent was evaporated under reduced pressure to give the compound    76, which was used in the subsequent reaction without further    purification.-   (2) The whole amount of the above compound 76 was dissolved in    toluene (65 ml), and thereto was added pinacol (2.24 g). The mixture    was stirred at room temperature under argon atmosphere for 17 hours.    The reaction solution was poured into water, and the mixture was    extracted with ethyl acetate, and the extract was washed with brine,    dried over magnesium sulfate. The solvent was evaporated under    reduced pressure to give the compound 7 (10.4 g) as a yellow    semisolid, which was used in the subsequent reaction without further    purification. APCI-Mass m/Z 569 (M+H).

REFERENCE EXAMPLE 4 5-Bromo-2-methylbenzaldehyde

-   (1) Methyl 5-bromo-2-methylbenzoate (see Japanese Unexamined Patent    Publication No. 9-263549) (16.12 g) was dissolved in methanol (100    ml), and thereto was added 10% aqueous sodium hydroxide solution (50    ml). The mixture was stirred at 50° C. for 40 minutes. Under    ice-cooling, the mixture was adjusted to pH 1 by addition of 10%    aqueous hydrochloric acid solution, and diluted with water.    Precipitated powder was collected by filtration, and dried to give    5-bromo-2-methylbenzoic acid (14.1 g). ESI-Mass m/Z 213/215 (M−H).-   (2) The above 5-bromo-2-methylbenzoic acid (10.0 g) was suspended in    dichloromethane (100 ml), and thereto were added oxalyl chloride    (8.1 ml) and N,N-dimethylformamide (2 drops). The mixture was    stirred at room temperature for 4 hours. The solvent was evaporated    under reduced pressure to give 5-bromo-2-methylbenzoyl chloride.    This benzoyl chloride was dissolved in dichloromethane (200 ml), and    thereto was added N,O-dimethylhydroxylamine hydrochloride (12.3 g).    To the mixture was added dropwise triethylamine (20 ml) at 0° C.,    and the mixture was stirred at room temperature overnight. The    solvent was evaporated under reduced pressure, and the residue was    extracted with ethyl acetate, and washed successively with water,    10% aqueous hydrochloric acid solution, water, a saturated aqueous    sodium hydrogen carbonate solution, and brine. The extract was dried    over sodium sulfate, and the solvent was evaporated under reduced    pressure to give N-methoxy-N-methyl-5-bromo-2-methylbenzamide    (12.25 g) as oil. APCI-Mass m/Z 258/260 (M+H).-   (3) A solution of the above    N-methoxy-N-methyl-5-bromo-2-methylbenzamide (12.2 g) in    tetrahydrofuran (100 ml) was cooled to −78° C. under argon    atmosphere. To the mixture was added dropwise diisobutyl aluminum    hydride (1.0 M toluene solution, 75 ml), and the mixture was stirred    at the same temperature for one hour. 10% aqueous hydrochloric acid    solution (50 ml) was added thereto, and the mixture was warmed to    room temperature. The mixture was extracted with ethyl acetate    twice, and washed successively with a saturated aqueous sodium    hydrogen carbonate solution and brine. The extract was dried over    magnesium sulfate, and the solvent was evaporated under reduced    pressure. The residue was solidified to give    5-bromo-2-methylbenzaldehyde (8.73 g). APCI-Mass m/Z 213/215 (M+H+    MeOH—H₂O).

REFERENCE EXAMPLE 5 5-Bromo-2-chloro-1-(5-ethyl-2-thienylmethyl)benzene

-   (1) 5-Bromo-2-chlorobenzoic acid (5.00 g) was suspended in    dichloromethane (10 ml), and thereto were added oxalyl chloride    (2.2 ml) and N,N-dimethylformamide (2 drops). The mixture was    stirred at room temperature for 6 hours. The solvent was evaporated    under reduced pressure to give 5-bromo-2-chlorobenzoyl chloride.    This compound and 2-ethylthiophene (2.38 g) were dissolved in    dichloromethane (20 ml), and thereto was added aluminum chloride    (3.11 g) at 0° C. The mixture was stirred at the same temperature    for one hour. The reaction mixture was poured into a cold 10%    aqueous hydrochloric acid solution, and the mixture was extracted    with ethyl acetate. The extract was washed successively with 10%    aqueous hydrochloric acid solution, water, a saturated aqueous    sodium hydrogen carbonate solution, and brine, and dried over    magnesium sulfate. The solvent was evaporated under reduced    pressure, the residue was purified by silica gel column    chromatography (hexane:ethyl acetate=100:1) to give    5-bromo-2-chlorophenyl 5-ethyl-2-thienyl ketone (5.29 g) as an oil.    APCI-Mass m/Z 329/331 (M+H).-   (2) A solution of the above 5-bromo-2-chlorophenyl 5-ethyl-2-thienyl    ketone (5.29 g) in dichloromethane (50 ml)—acetonitrile (50 ml) was    cooled under ice-cooling, and thereto were added dropwise    triethylsilane (7.69 ml) and boron trifluoride.diethyl ether complex    (6.1 ml). Subsequently, the mixture was stirred at room temperature    for 3.5 hours, and was cooled again under ice-cooling. To the    mixture was added a saturated aqueous sodium hydrogen carbonate    solution, and the mixture was extracted with chloroform, washed with    brine, and dried over magnesium sulfate. The solvent was evaporated    under reduced pressure, and the residue was purified by silica gel    column chromatography (hexane) to give    5-bromo-2-chloro-1-(5-ethyl-2-thienylmethyl)benzene (4.52 g) as a    colorless liquid.

REFERENCE EXAMPLE 6 3-Bromo-1-(5-n-propyl-2-thienylmethyl)benzene

3-Bromobenzoic acid and 2-n-propylthiophene were used and treated in amanner similar to Reference Example 5 to give the target compound.

REFERENCE EXAMPLE 7 5-Bromo-(5-ethyl-2-thienylmethyl)₂-methoxybenzene

-   (1) A solution of 2-ethylthiophene (3.00 g) in tetrahydrofuran    (36 ml) was cooled to 0° C. under argon atmosphere, and thereto was    added dropwise n-butyl lithium (1.56 M hexane solution, 17.1 ml).    The mixture was stirred at the same temperature for 30 minutes, and    cooled to −78° C., and thereto was added dropwise a suspension of    5-bromo-2-methoxybenzaldehyde (5.74 g) in tetrahydrofuran (60 ml).    The mixture was stirred at the same temperature for 2 hours, warmed    to 0° C., and thereto was added a saturated aqueous ammonium    chloride solution. The mixture was extracted with ethyl acetate, and    the extract was washed with brine, and dried over sodium sulfate.    The solvent was evaporated under reduced pressure. The residue was    purified by silica gel column chromatography (hexane:ethyl    acetate=100:0-85:15) to give    5-bromo-2-methoxyphenyl-5-ethyl-2-thienylmethanol (5.99 g) as a pale    yellow syrup. APCI-Mass m/Z 309/311 (M+H—H₂O)-   (2) The above 5-bromo-2-methoxyphenyl-5-ethyl-2-thienylmethanol was    treated in a manner similar to Reference Example 1-(2) to give    5-bromo-(5-ethyl-2-thienylmethyl)-2-methoxybenzene as oil. APCI-Mass    m/Z 311/313 (M+H).

REFERENCE EXAMPLE 8 3-Bromo-1-(5-ethyl-2-thienylmethyl)-4-methoxybenzene

2-Ethylthiophene and 3-bromo-4-methoxybenzaldehyde were used and treatedin a manner similar to Reference Example 7 to give the target compound.

REFERENCE EXAMPLE 9 3-Bromo-1-(4-n-propyl-2-thienylmethyl)benzene

-   (1) 3-n-Propylthiophene and 3-bromobenzaldehyde were used and    treated in a manner similar to Reference Example 7-(1) to give    3-bromophenyl-4-n-propyl-2-thienyl methanol. APCI-Mass m/Z 293/295    (M+H—H₂O).-   (2) A solution of the above 3-bromophenyl-4-n-propyl-2-thienyl    methanol (2.4 g) in acetonitrile (10 ml) was added dropwise to a    mixed solution of chlorotrimethylsilane (4.54 ml) and sodium iodide    (5.36 g) in acetonitrile (10 ml) at 0° C., over a period of 2 hours.    The mixture was further stirred at room temperature for 5 minutes,    and cooled again to 0° C. An aqueous solution (10 ml) of sodium    hydroxide (1.0 g) was added thereto, and the mixture was stirred at    0° C. for 0.5 hours. The mixture was extracted with ethyl acetate,    washed successively with an aqueous sodium thiosulfate solution,    water and brine, and dried over sodium sulfate. The solvent was    evaporated under reduced pressure, and the residue was purified by    silica gel column chromatography (hexane) to give    3-bromo-1-(4-n-propyl-2-thienyl)benzene (1.97 g) as colorless oil.

REFERENCE EXAMPLE 105-Bromo-2-chloro-1-(5-n-propyl-2-thienylmethyl)benzene

5-Bromo-2-chlorobenozoic acid and 2-n-propylthiophene were used andtreated in a manner similar to Reference Example 5 to give the targetcompound.

REFERENCE EXAMPLE 115-Bromo-2-methoxy-1-(5-n-propyl-2-thienylmethyl)benzene

2-n-Propylthiophene and 5-bromo-2-methoxybenzaldehyde were used andtreated in a manner similar to Reference Example 7 to give the targetcompound. APCI-Mass m/Z 325/327 (M+H)

REFERENCE EXAMPLE 12 3-Bromo-1-(4-ethyl-2-thienylmethyl)benzene

3-Ethylthiophene and 3-bromobenzaldehyde were used and treated in amanner similar to Reference Example 9 to give the target compound.APCI-Mass m/Z 281/283 (M+H).

REFERENCE EXAMPLE 13 3-Bromo-1-(4-chloro-5-ethyl-2-thienylmethyl)benzene

-   (1) To a solution of 5-ethyl-2-thiophenecarboxaldehyde (6.0 g) in    N,N-dimethylformamide (60 ml) was added N-chlorosuccinimide (8.57    g), and the mixture was stirred at room temperature for 2 hours, and    subsequently stirred under heating at 60° C. for 2 hours.    N-chlorosuccinimide (4.00 g) was further added thereto, and the    mixture was further stirred under heating at 60° C. for 2 hours. The    reaction mixture was poured into water, and the mixture was    extracted with ethyl acetate, washed with brine, and dried over    sodium sulfate. The solvent was evaporated under reduced pressure,    and the residue was purified by silica gel column chromatography    (hexane:ethyl acetate=33:1) to give    4-chloro-5-ethyl-2-thiophenecarboxaldehyde (3.1 g) as colorless oil.-   (2) The above 4-chloro-5-ethyl-2-thiophenecarboxaldehyde was treated    in a manner similar to Reference Example 1 to give    3-bromo-1-(4-chloro-5-ethyl-2-thienylmethyl)benzene as yellow oil.    APCI-Mass m/Z 347/349 (M+H+ MeOH)

REFERENCE EXAMPLE 145-Bromo-2-chloro-1-(4,5,6,7-tetrahydrobenzo[b]thiophen-2-ylmethyl)benzene

-   (1) To a solution of 4-keto-4, 5, 6, 7-tetrahydrothianaphthene    (9.83 g) in ethylene glycol (100 ml) were added hydrazine hydrate    (10.4 ml) and potassium hydroxide (13.0 g), and the mixture was    stirred under argon atmosphere at 190° C. for 4 hours. The reaction    mixture was cooled to room temperature, and poured into water, and    the mixture was extracted with ethyl acetate. The extract was washed    with water, and dried over sodium sulfate. The solvent was    evaporated under reduced pressure, and the residue was purified by    silica gel column chromatography (hexane) to give    4,5,6,7-tetrahydrothianaphthene (2.75 g) as colorless oil.-   (2) The above 4,5,6,7-tetrahydrothianaphthene was treated in a    manner similar to Reference Example 5 to give    5-bromo-2-chloro-1-(4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl    methyl)benzene as a colorless solid. APCI-Mass m/Z 341/343 (M+H).

REFERENCE EXAMPLE 155-Bromo-2-chloro-1-(5-ethyl-4-methyl-2-thienylmethyl)-benzene

-   (3) 2-Acetyl-3-methylthiophene was treated in a manner similar to    Reference Example 14 to give the target compound. APCI-Mass m/Z    329/331 (M+H).

REFERENCE EXAMPLE 165-Bromo-2-chloro-1-(2-thieno[3,2-b]thienylmethyl)benzene

-   (1) 5-Bromo-2-chlorobenzoic acid was treated in a manner similar to    Reference Example 4-(2) and (3) to give    5-bromo-2-chlorobenzaldehyde. APCI-Mass m/Z 233/235 (M+H+ MeOH—H₂O).-   (2) The above 5-bromo-2-chlorobenzaldehyde and    thieno[3,2-b]thiophene (see Fuller, L.; Iddon, B.; Smith, K. A. J.    Chem. Soc. Perkin Trans 1 1997, 3465-3470) were treated in a manner    similar to Reference Example 9 to give    5-bromo-2-chloro-1-(2-thieno[3,2-b]thienylmethyl)benzene as    colorless oil. APCI-Mass m/Z 343/345 (M+H).

REFERENCE EXAMPLE 175-Bromo-2-chloro-1-(5-chloro-2-thienylmethyl)benzene

2-Chlorothiophene was treated in a manner similar to Reference Example 5to give the target compound.

REFERENCE EXAMPLE 185-Bromo-2-chloro-1-(5-phenylmethyl-2-thienylmethyl)benzene

2-Benzoylthiophene was treated in a manner similar to Reference Example14 to give the target compound. APCI-Mass m/Z 377/379 (M+H).

REFERENCE EXAMPLE 195-Bromo-2-chloro-1-(5-(2-thienyl)-2-thienylmethyl)benzene

2,2′-Bithiophene and 5-bromo-2-chlorobenzaldehyde obtained in ReferenceExample 16-(1) were used and treated in a manner similar to ReferenceExample 9 to give the target compound. APCI-Mass m/Z 369/371 (M+H).

REFERENCE EXAMPLE 205-Bromo-1-(5-(5-chloro-2-thienyl)-2-thienylmethyl)-2-methylbenzene

-   (1) To a solution of 2-bromo-5-chlorothiophene (4.11 g),    thiophene-2-boronic acid (4.00 g),    tetrakis(triphenylphosphine)palladium (0) (1.20 g) and 2M aqueous    sodium carbonate solution (31.3 ml) in dimethoxyethane (100 ml) was    heated under reflux under argon atmosphere for 2.5 hours. The    reaction mixture was cooled, and extracted with ethyl acetate. The    solvent was evaporated under reduced pressure, and the residue was    purified by silica gel column chromatography (hexane) to give    2-(5-chloro-2-thienyl)thiophene (3.37 g) as pale yellow oil.-   (2) The above 2-(5-chloro-2-thienyl)thiophene and    5-bromo-2-methylbenzoic acid obtained in Reference Example 4-(1)    were used and treated in a manner similar to Reference Example 5 to    give 5-bromo-1-(5-(5-chloro-2-thienyl)-2-thienylmethyl)-2-methyl    benzene as a colorless solid. APCI-Mass m/Z 383/385 (M+H).

REFERENCE EXAMPLE 215-Bromo-2-chloro-1-(4-chloro-5-ethyl-2-thienylmethyl)-benzene

2-Acetyl-3-chlorothiophene (see Japanese Unexamined Patent PublicationNo. 2000-34230) was treated in a manner similar to Reference Example 14to give the target compound. APCI-Mass m/Z 347/349 (M+H).

REFERENCE EXAMPLE 22 5-Chloro-4-methylthiophene

The target compound was prepared according to a method described inJapanese Unexamined Patent Publication No. 10-324632.

REFERENCE EXAMPLE 235-Bromo-2-chloro-1-(5-(5-chloro-2-thienyl)-2-thienylmethyl) benzene

2-(5-Chloro-2-thienyl)thiophene and 5-bromo-2-chlorobenzoic acid weretreated in a manner similar to Reference Example 5 to give the targetcompound.

REFERENCE EXAMPLE 245-Bromo-2-chloro-1-(5-trifluoromethyl-2-thienylmethyl)-benzene

2-Trifluoromethylthiophene (see Japanese Unexamined Patent PublicationNo. 2000-34239) and 5-bromo-2-chlorobenzaldehyde obtained in ReferenceExample 16-(1) were treated in a manner similar to Reference Example 7to give the target compound.

REFERENCE EXAMPLE 255-Bromo-2-chloro-1-(5-(2-pyridyl)-2-thienylmethyl)benzene

-   (1) 2-(2-Pyridyl)thiophene and 5-bromo-2-chlorobenzaldehyde obtained    in Reference Example 16—(1) were treated in a manner similar to    Reference Example 7-(1) to give    5-bromo-2-chlorophenyl-5-(2-pyridyl)-2-thienylmethanol as colorless    powder. APCI-Mass m/Z 380/382 (M+H)-   (2) A solution of the above    5-bromo-2-chlorophenyl-5-(2-pyridyl)-2-thienylmethanol (3.52 g) in    trifluoroacetic acid (45 ml) was added to a solution of sodium    borohydride (1.75 g) in trifluoroacetic acid (45 ml), and the    mixture was stirred at room temperature for 4 hours. Trifluoroacetic    acid was evaporated under reduced pressure. The residue was basified    with an aqueous potassium hydroxide solution, and extracted with    diethyl ether. The extract was dried over sodium sulfate, and the    solvent was evaporated under reduced pressure. The residue was    purified by silica gel column chromatography (hexane:ethyl    acetate=9:1-4:1) to give    5-bromo-2-chloro-1-(5-(2-pyridyl)-2-thienylmethyl)benzene (2.42 g)    as a colorless solid. APCI-Mass m/Z 364/366 (M+H).

REFERENCE EXAMPLE 265-Bromo-1-(5-chloro-2-thienylmethyl)-2-phenylbenzene

-   (1) 5-Bromo-2-iodobenzoic acid (see Jorg Frahn, A.-Dieter Schluter    Synthesis 1997, 1301-1304) and 2-chlorothiophene were treated in a    manner similar to Reference Example 5 to give    5-bromo-1-(5-chloro-2-thienylmethyl)-2-iodobenzene as colorless oil.-   (2) To a solution of the above    5-bromo-1-(5-chloro-2-thienylmethyl)-2-iodobenzene (1.0 g) in    dimethoxyethane (10 ml) were added phenylboronic acid (310 mg),    bis(triphenylphosphine)palladium (II) dichloride (85 mg) and 2M    aqueous sodium carbonate solution (3.8 ml), and the mixture was    stirred at 50° C. overnight. Added thereto was a saturated aqueous    sodium hydrogen carbonate solution and the mixture was extracted    with ethyl acetate and dried over sodium sulfate. The solvent was    evaporated under reduced pressure, and the residue was purified by    silica gel column chromatography (hexane) to give    5-bromo-1-(5-chloro-2-thienylmethyl)-2-phenylbenzene (683 mg) as    oil.

REFERENCE EXAMPLE 27 2-Chlorothieno[3,2-b]thiophene

-   (1) A solution of thieno[3,2-b]thiophene (see Fuller, L.; Iddon, B.;    Smith, K. A. J. Chem. Soc. Perkin Trans 1 1997, 3465-3470) (1.27 g)    in tetrahydrofuran (30 ml) was cooled to −78° C. under argon    atmosphere, and thereto was added dropwise n-butyl lithium (1.59 M    hexane solution, 5.70 ml). The mixture was stirred at 0° C. for 30    minutes, and cooled again to −78° C. Added thereto was a solution of    hexachloroethane (2.14 g) in tetrahydrofuran (5 ml). The mixture was    stirred at the same temperature for one hour, and warmed to 0° C.    Added thereto was a saturated aqueous ammonium chloride solution,    and the mixture was extracted with ethyl acetate. The solvent was    evaporated under reduced pressure. The residue was purified by    silica gel column chromatography (hexane) to give    2-Chlorothieno[3,2-b]thiophene (1.19 g) as a solid.

REFERENCE EXAMPLE 281-(Benzo[b]thiophen-2-ylmethyl)-5-bromo-2-methoxybenzene

Thianaphthene was treated in a manner similar to Reference Example 7 togive the target compound. ESI-Mass m/Z 331/333 (M−H).

REFERENCE EXAMPLE 291-(Benzo[b]thiophen-2-ylmethyl)-5-bromo-2-chlorobenzene

Thianaphthene and 5-bromo-2-chlorobenzaldehyde obtained in ReferenceExample 16-(1) were treated in a manner similar to Reference Example 7to give the target compound.

REFERENCE EXAMPLE 303-Bromo-1-(5-methylbenzo[b]thiophen-2-ylmethyl)benzene

5-Methylbenzo[b]thiophene and 3-bromobenzaldehyde were treated in amanner similar to Reference Example 7 to give the target compound.

REFERENCE EXAMPLE 313-Bromo-1-(6-fluorobenzo[b]thiophen-2-ylmethyl)benzene

-   (1) To a solution of 2,4-difluorobenzaldehyde (5.0 g) in    dimethylsulfoxide (100 ml) were added methyl thioglycolate (3.45 ml)    and triethylamine (10 ml), and the mixture was stirred at 80° C.    overnight. The reaction mixture was poured into ice-cold water. The    mixture was extracted with ethyl acetate, washed with water and    brine, and dried over sodium sulfate. The solvent was evaporated    under reduced pressure. The residue was purified by silica gel    column chromatography (hexane:ethyl acetate=7:1) to give    6-fluoro-2-methoxycarbonylbenzo[b]thiophene (1.32 g) as colorless    powder. GC-EI-Mass m/Z 210 (M).-   (2) The above 6-fluoro-2-methoxycarbonylbenzo[b]thiophene was    treated in a manner similar to Reference Example 4-(1) to give    6-fluorobenzo[b]thiophen-2-ylcarboxylic acid as colorless powder.    ESI-Mass m/Z 195 (M−H).-   (3) The above 6-fluorobenzo[b]thiophen-2-ylcarboxylic acid was    treated in a manner similar to Reference Example 4-(2) to give    6-fluoro-2-(N-methoxy-N-methylcarbamoyl)benzo[b]thiophene as    colorless powder. APCI-Mass m/Z 240 (M+H).-   (4) A solution of 1,3-dibromobenzene (493 mg) in tetrahydro-furan    (10 ml) was cooled to −78° C. under argon atmosphere, and thereto    was added dropwise n-butyl lithium (2.44 M hexane solution, 0.86    ml). The reaction mixture was stirred at the same temperature for 30    minutes, and thereto was added dropwise a solution of the above    6-fluoro-2-(N-methoxy-N-methylcarbamoyl)benzo[b]thiophene (500 mg)    in tetrahydrofuran (3 ml). The mixture was warmed to room    temperature, and added thereto was a saturated aqueous ammonium    chloride solution. The mixture was extracted with ethyl acetate, and    dried over magnesium sulfate. The solvent was evaporated under    reduced pressure. The residue was purified by silica gel column    chromatography (hexane:ethyl acetate=95:5-85:15) to give    3-bromophenyl 6-fluorobenzo[b]thiophen-2-yl ketone (479 mg) as a    pale yellow solid. APCI-Mass m/Z 335/337 (M+NH₄).-   (5) The above 3-bromophenyl 6-fluorobenzo[b]thiophen-2-yl ketone was    treated in a manner similar to Reference Example 5-(2) to give    3-bromo-1-(6-fluorobenzo[b]thiophen-2-ylmethyl)benzene as a    colorless solid.

REFERENCE EXAMPLE 321-(Benzo[b]thiophen-2-ylmethyl)-3-bromo-4-fluorobenzene

Thianaphthene and 3-bromo-4-fluorobenzaldehyde were treated in a mannersimilar to Reference Example 7 to give the target compound.

REFERENCE EXAMPLE 331-(Benzo[b]thiophen-2-ylmethyl)-5-bromo-2-ethoxybenzene

Thianaphthene and 5-bromo-2-ethoxybenzaldehyde were treated in a mannersimilar to Reference Example 7 to give the target compound.

REFERENCE EXAMPLE 341-(Benzo[b]thiophen-2-ylmethyl)-5-bromo-2-fluorobenzene

Thianaphthene and 5-bromo-2-fluorobenzaldehyde were treated in a mannersimilar to Reference Example 7 to give the target compound.

REFERENCE EXAMPLE 352-(Benzo[b]thiophen-2-ylmethyl)-4-bromo-1-methoxy-naphthalene

2,4-Dibromo-1-methoxynaphthalene (see J. Clayden, et al. Org. Lett., 5,(2003) 831) and benzo[b]thiophene-2-carboxaldehyde were treated in amanner similar to Reference Example 1 to give the target compound.

REFERENCE EXAMPLE 363-Bromo-1-(5-trifluoromethylbenzo[b]thiophen-2-ylmethyl)benzene

5-Trifluoromethylbenzo[b]thiophen-2-ylcarboxylic acid was treated in amanner similar to Reference Example 31-(3), (4), and (5) to give thetarget compound.

REFERENCE EXAMPLE 373-Bromo-1-(3-methylbenzo[b]thiophen-2-ylmethyl)benzene

3-Methylbenzo[b]thiophene-2-carboxaldehyde was treated in a mannersimilar to Reference Example 1 to give the target compound.

REFERENCE EXAMPLE 383-Bromo-1-(5-fluorobenzo[b]thiophen-2-ylmethyl)benzene

2,5-Difluorobenzaldehyde was treated in a manner similar to ReferenceExample 31 to give the target compound.

REFERENCE EXAMPLE 391-(Benzo[b]thiophen-2-ylmethyl)-3-bromo-4-methylbenzene

-   (1) 3-Bromo-4-methylbenzoic acid was treated in a manner similar to    Reference Example 4-(2) and (3) to give 3-bromo-4-methylbenzaldehyde    as colorless crystals. APCI-Mass m/Z 213/215 (M+H+MeOH).-   (2) The above 3-bromo-4-methylbenzaldehyde and thianaphthene were    treated in a manner similar to Reference Example 7 to give    (Benzo[b]thiophen-2-ylmethyl)-3-bromo-4-methylbenzene as a colorless    solid.

REFERENCE EXAMPLE 401-(Benzo[b]thiophen-2-ylmethyl)-3-bromo-5-methylbenzene

3,5-Dibromotoluene and benzo[b]thiophene-2-carboxaldehyde were treatedin a manner similar to Reference Example 1 to give the target compound.

REFERENCE EXAMPLE 415-Bromo-2-chloro-1-(5-methylbenzo[b]thiophen-2-ylmethyl)benzene

5-Methylbenzo[b]thiophene and 5-bromo-2-chlorobenzaldehyde obtained inReference Example 16-(1) were treated in a manner similar to ReferenceExample 7 to give the target compound.

REFERENCE EXAMPLE 425-Bromo-2-chloro-1-(7-methylbenzo[b]thiophen-2-ylmethyl)benzene

7-Methylbenzo[b]thiophene (see Tilak, B. D. Tetrahedron 9 (1960)76-95)and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example16-(1) were treated in a manner similar to Reference Example 7 to givethe target compound.

REFERENCE EXAMPLE 435-Bromo-2-chloro-1-(5-chlorobenzo[b]thiophen-2-ylmethyl)benzene

5-Chlorobenzo[b]thiophene (see Tilak, B. D. Tetrahedron 9 (1960)76-95)and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example16-(1) were treated in a manner similar to Reference Example 7 to givethe target compound.

REFERENCE EXAMPLE 445-Bromo-2-chloro-1-(5,7-dimethylbenzo[b]thiophen-2-ylmethyl)benzene

5,7-Dimethylbenzo[b]thiophene (see Yoshimura, Y. et al., J. Med. Chem.43 (2000) 2929-2937) and 5-bromo-2-chlorobenzaldehyde obtained inReference Example 16-(1) were treated in a manner similar to ReferenceExample 7 to give the target compound.

REFERENCE EXAMPLE 451-(Benzo[b]thiophen-2-ylmethyl)-5-bromo-2-methylbenezene

-   (1) A solution of thianaphthene (543 mg) in diethyl ether (20 ml)    was cooled to 0° C. under argon atmosphere, and thereto was added    dropwise n-butyl lithium (2.44 M hexane solution, 1.74 ml). The    reaction mixture was stirred at the same temperature for 3 hours.    The reaction mixture was added dropwise to a solution of    N-methoxy-N-methyl-5-bromo-2-methylbenzamide (1.15 g) obtained in    Reference Example 4-(2) in diethyl ether (10 ml) cooled to −78° C.    The mixture was warmed to room temperature and stirred for one hour.    Added thereto was a saturated aqueous ammonium chloride solution.    The mixture was extracted with ethyl acetate, washed with brine, and    dried over sodium sulfate. The solvent was evaporated under reduced    pressure. The residue was purified by silica gel column    chromatography (hexane:ethyl acetate=100:0-95:5) to give    5-bromo2-methylphenyl benzo[b]thiophen-2-yl ketone (995 mg) as a    pale yellow syrup. APCI-Mass m/Z 331/333 (M+H).-   (2) The above 5-bromo2-methylphenyl benzo[b]thiophen-2-yl ketone was    treated in a manner similar to Reference Example 5-(2) to give    1-(benzo[b]thiophen-2-ylmethyl)-5-bromo-2-methylbenezene as    colorless oil.

REFERENCE EXAMPLE 465-Bromo-2-chloro-1-(6-methoxybenzo[b]thiophen-2-ylmethyl)-benzene

6-Methoxybenzo[b]thiophene (see WO 97/25033) and5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1) weretreated in a manner similar to Reference Example 7 to give the targetcompound.

REFERENCE EXAMPLE 475-Bromo-2-chloro-1-(6-chlorobenzo[b]thiophen-2-ylmethyl)-benzene

-   (1) 4-Chloro-2-fluorobenzaldehyde was treated in a manner similar to    Reference Example 31-(1) and (2) to give    6-chlorobenzo[b]thiophen-2-ylcarboxylic acid as colorless crystals.    ESI-Mass m/Z 211/213 (M−H).-   (2) A solution of the above 6-chlorobenzo[b]thiophen-2-ylcarboxylic    acid (3.0 g) and copper powder (1.2 g) in quinoline (20 ml) was    stirred at 210° C. for 40 minutes. The mixture was cooled to room    temperature and diluted with diethyl ether, and insoluble materials    were filtered off. The filtrate was washed successively with 10%    aqueous hydrochloric acid solution and brine, and dried over    magnesium sulfate. The solvent was evaporated under reduced    pressure, and the residue was purified by silica gel column    chromatography (hexane) to give 6-chlorobenzo[b]thiophene (1.79 g)    as colorless crystals.-   (3) The above 6-chlorobenzo[b]thiophene and    5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1)    were treated in a manner similar to Reference Example 7 to give    5-bromo-2-chloro-1-(6-chlorobenzo[b]thiophen-2-ylmethyl)-benzene as    colorless crystals.

REFERENCE EXAMPLE 485-Bromo-2-chloro-1-(6-trifluoromethylbenzo[b]thiophen-2-ylmethyl)benzene

2-Fluoro-4-trifluoromethylbenzaldehyde was treated in a manner similarto Reference Example 47 to give the target compound.

REFERENCE EXAMPLE 491-Benzo[b]thiophen-2-ylmethyl)-3-bromo-4-chlorobenzene

3-Bromo-4-chlorobenzoic acid was treated in a manner similar toReference Example 39 to give the target compound.

REFERENCE EXAMPLE 505-Bromo-2-chloro-1-(6-fluorobenzo[b]thiophen-2-ylmethyl)-benzene

2,4-Difluorobenzaldehyde was treated in a manner similar to ReferenceExample 47 to give the target compound.

REFERENCE EXAMPLE 515-Bromo-2-fluoro-1-(6-fluorobenzo[b]thiophen-2-ylmethyl)-benzene

6-Fluorobenzo[b]thiophene produced in the preparation process ofReference Example 50 and 5-bromo-2-fluorobenzaldehyde were treated in amanner similar to Reference Example 7 to give the target compound.

REFERENCE EXAMPLE 521-(Benzo[b]thiophen-2-ylmethyl)-3-bromo-5-chlorobenzene

1-Chloro-3,5-dibromobenzene and benzo[b]thiophene-2-carboxaldehyde weretreated in a manner similar to Reference Example 1 to give the targetcompound.

REFERENCE EXAMPLE 535-Bromo-2-chloro-1-(7-methoxybenzo[b]thiophen-2-ylmethyl)-benzene

7-Methoxybenzo[b]thiophene (see WO 02/094262) and5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1) weretreated in a manner similar to Reference Example 9 to give the targetcompound. APCI-Mass m/Z 367/369 (M+H).

REFERENCE EXAMPLE 545-Bromo-2-chloro-1-(5-methoxybenzo[b]thiophen-2-ylmethyl)-benzene

5-Methoxybenzo[b]thiophene (see WO 97/25033) and5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1) weretreated in a manner similar to Reference Example 9 to give the targetcompound. APCI-Mass m/Z 367/369 (M+H).

REFERENCE EXAMPLE 555-Bromo-2-chloro-1-(5-fluorobenzo[b]thiophen-2-ylmethyl)-benzene

2,5-Difluorobenzaldehyde was treated in a manner similar to ReferenceExample 47 to give the target compound.

REFERENCE EXAMPLE 565-Bromo-2-chloro-1-(7-fluoro-6-methylbenzo[b]thiophen-2-ylmethyl)benzene

2,3-Difluoro-4-methylbenzaldehyde was treated in a manner similar toReference Example 47 to give the target compound. APCI-Mass m/Z 369/371(M+H).

REFERENCE EXAMPLE 575-Bromo-2-chloro-1-(4-fluorobenzo[b]thiophen-2-ylmethyl)-benzene

2,6-Difluorobenzaldehyde was treated in a manner similar to ReferenceExample 47 to give the target compound.

REFERENCE EXAMPLE 585-Bromo-2-chloro-1-(7-fluorobenzo[b]thiophen-2-ylmethyl)-benzene

2,3-difluorobenzaldehyde was treated in a manner similar to ReferenceExample 47 to give the target compound.

REFERENCE EXAMPLE 595-Bromo-2-chloro-1-(4-chlorobenzo[b]thiophen-2-ylmethyl)-benzene

2-Chloro-6-fluorobenzaldehyde was treated in a manner similar toReference Example 47 to give the target compound.

REFERENCE EXAMPLE 605-Bromo-2-fluoro-1-(5-fluorobenzo[b]thiophen-2-ylmethyl)-benzene

5-Fluorobenzo[b]thiophene produced in the preparation process ofReference Example 55 and 5-bromo-2-fluorobenzaldehyde were treated in amanner similar to Reference Example 7 to give the target compound.

REFERENCE EXAMPLE 613-Bromo-2-chloro-1-(benzo[b]thiophen-2-ylmethyl)benzene

-   (1) 3-Bromo-2-chlorobenzoic acid (see Frederic Gohier et al., J.    Org. Chem. (2003) δ 2030-2033.) was treated in a manner similar to    Reference Example 4-(2) to give    N-methoxy-N-methyl-3-bromo-2-chlorobenzamide as oil. APCI-Mass m/Z    278/280/282 (M+H).-   (2) The above N-methoxy-N-methyl-3-bromo-2-chlorobenzamide was    treated in a manner similar to Reference Example 45 to give    3-bromo-2-chloro-1-(benzo[b]thiophen-2-ylmethyl)benzene as a    colorless solid.

REFERENCE EXAMPLE 621-(Benzo[b]thiophen-2-ylmethyl)-5-bromo-2-ethylbenzene

-   (1) To a solution of 2-ethylbenzoic acid (10.0 g) in dichloromethane    (50 ml) were added oxalyl chloride (7.0 ml) and    N,N-dimethylformamide (3 drops) and the mixture was stirred at room    temperature for 3 hours. The solvent was evaporated under reduced    pressure to give a corresponding acid chloride. The acid chloride    was dissolved in methanol (60 ml) and the mixture was stirred at    room temperature for 3 hours, and then, the solvent was evaporated    under reduced pressure. The residue was dissolved in diethyl ether,    and washed successively with a saturated aqueous sodium hydrogen    carbonate solution and brine, and dried over sodium sulfate. The    solvent was evaporated under reduced pressure to give methyl    2-ethylbenzoate, which was used in the subsequent step without    further purification.-   (2) The above methyl 2-ethylbenzoate was mixed with molecular sieve    13× (powder, 70 g), and while stirring the mixture, bromine (5.2 ml)    was added dropwise thereto at 80° C. The mixture was further stirred    at the same temperature for 1.5 hours. The mixture was cooled to    room temperature, and added thereto were potassium carbonate (7.4    g), water (70 ml) and methanol (350 ml), and the mixture was stirred    for 8 hours. Insoluble materials were filtered off, and suspended in    a mixed solution of methanol (500 ml)-water (500 ml), and the    mixture was stirred at room temperature overnight. Insoluble    materials were filtered off and the filtrate was combined with the    previously obtained filtrate, and the solvent was evaporated under    reduced pressure. The residue was extracted with ethyl acetate, and    the extract was washed with brine, and dried over sodium sulfate.    The solvent was evaporated under reduced pressure, and the residue    was distilled under reduced pressure, to give methyl    5-bromo-2-ethylbenzoate (2.44 g). APCI-Mass m/Z 260/262 (M+NH₄).-   (3) The above methyl 5-bromo-2-ethylbenzoate was treated in a manner    similar to Reference Example 4-(1) and (2) to give    N-methoxy-N-methyl-5-bromo-2-ethylbenzamide as colorless oil.    APCI-Mass m/Z 272/274 (M+H).-   (4) The above N-methoxy-N-methyl-5-bromo-2-ethylbenzamide and    thianaphthene were treated in a manner similar to Reference Example    45 to give 1-(Benzo[b]thiophen-2-ylmethyl)-5-bromo-2-ethylbenzene as    oil.

REFERENCE EXAMPLE 631-(Benzo[b]thiophen-2-ylmethyl)-5-bromo-2-trifluoromethyl-benzene

-   (1) 5-Bromo-2-iodobenzoic acid (see Jorg Frahn, A.-Dieter Schluter    Synthesis 1997, 1301-1304) was treated in a manner similar to    Reference Example 4-(2) to give    N-methoxy-N-methyl-5-bromo-2-iodobenzamide as a pale yellow solid.    APCI-Mass m/Z 370/372 (M+H).-   (2) To a solution of the above    N-methoxy-N-methyl-5-bromo-2-iodobenzamide (2.67 g) in    N-methyl-2-pyrrolidinone (12 ml) were added copper (I) bromide (124    mg) and methyl fluorosulfonyl(difluoro)acetate (1.34 ml), and the    mixture was stirred under heating for 1.5 hours. The reaction    mixture was cooled to room temperature, and then, a diluted aqueous    ammonia was added thereto, and the mixture was extracted with    ethylacetate. The extract was washed with water and brine, and dried    over sodium sulfate. The solvent was evaporated under reduced    pressure. The residue was purified by silica gel column    chromatography (hexane:ethyl acetate=100:0-85:15) to give    N-methoxy-N-methyl-5-bromo-2-trifluoromethylbenzamide (1.59 g) as    colorless oil. APCI-Mass m/Z 312/314 (M+H).-   (3) The above N-methoxy-N-methyl-5-bromo-2-trifluoromethylbenzamide    and thianaphthene were treated in a manner similar to Reference    Example 45 to give    1-(Benzo[b]thiophen-2-ylmethyl)-5-bromo-2-trifluoromethylbenzene as    a colorless solid. ESI-Mass m/Z 369/371 (M−H).

REFERENCE EXAMPLE 645-Bromo-2-chloro-1-(5-phenyl-2-thienylmethyl)benzene

2-Phenylthiophene was treated in a manner similar to Reference Example 5to give the target compound. APCI-Mass m/Z 363/365 (M+H).

REFERENCE EXAMPLE 655-Bromo-2-chloro-1-(5-(4-methylphenyl)-2-thienylmethyl)-benzene

-   (1) 2-Iodothiophene and 4-methylphenylboronic acid were treated in a    manner similar to Reference Example 26-(2) to give    2-(4-methylphenyl)thiophene as colorless crystals. APCI-Mass m/Z 175    (M+H).-   (2) The above 2-(4-methylphenyl)thiophene was treated in a manner    similar to Reference Example 5 to give    5-bromo-2-chloro-1-(5-(4-methylphenyl)-2-thienylmethyl)-benzene as    colorless crystals. APCI-Mass m/Z 377/379 (M+H)

REFERENCE EXAMPLE 665-Bromo-2-chloro-1-(5-(2-fluorophenyl)-2-thienylmethyl)-benzene

-   (1) 2-Fluorobromobenzene and thiophene-2-boronic acid were treated    in a manner similar to Reference Example 26-(2) to give    2-(2-fluorophenyl)thiophene as a colorless liquid. (2) The above    2-(2-fluorophenyl)thiophene was treated in a manner similar to    Reference Example 5 to give    5-bromo-2-chloro-1-(5-(2-fluorophenyl)-2-thienylmethyl)-benzene as a    colorless solid. APCI-Mass m/Z 381/383 (M+H)

REFERENCE EXAMPLE 675-Bromo-2-chloro-1-(5-(4-fluorophenyl)-2-thienylmethyl)-benzene

-   (1) 2-Iodothiophene and 4-fluorophenylboronic acid were treated in a    manner similar to Reference Example 26-(2) to give    2-(4-fluorophenyl)thiophene as colorless powder.-   (2) The above 2-(4-fluorophenyl)thiophene was treated in a manner    similar to Reference Example 5 to give    5-bromo-2-chloro-1-(5-(4-fluorophenyl)-2-thienylmethyl)-benzene as    colorless powder.

REFERENCE EXAMPLE 685-Bromo-2-chloro-1-(5-(4-ethoxyphenyl)-2-thienylmethyl)-benzene

-   (1) 2-Bromothiophene and 4-ethoxyphenylboronic acid were treated in    a manner similar to Reference Example 20-(1) to give    2-(4-ethoxyphenyl)thiophene as a colorless solid. APCI-Mass m/Z 205    (M+H).-   (2) The above 2-(4-ethoxyphenyl)thiophene was treated in a manner    similar to Reference Example 5 to give    5-bromo-2-chloro-1-(5-(4-ethoxyphenyl)-2-thienylmethyl)-benzene as a    colorless solid. APCI-Mass m/Z 407/409 (M+H)

REFERENCE EXAMPLE 695-Bromo-2-chloro-1-(5-(3-ethoxyphenyl)-2-thienylmethyl)-benzene

-   (1) 2-Bromothiophene and 3-ethoxyphenylboronic acid were treated in    a manner similar to Reference Example 20-(1) to give    2-(3-ethoxyphenyl)thiophene as colorless oil. APCI-Mass m/Z 205    (M+H).-   (2) The above 2-(3-ethoxyphenyl)thiophene and    5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1)    were treated in a manner similar to Reference Example 9 to give    5-bromo-2-chloro-1-(5-(3-ethoxyphenyl)-2-thienylmethyl)-benzene as    colorless oil. APCI-Mass m/Z 407/409 (M+H).

REFERENCE EXAMPLE 705-Bromo-2-chloro-1-(5-(2-ethoxyphenyl)-2-thienylmethyl)-benzene

-   (1) 2-Iodothiophene and 2-ethoxyphenylboronic acid were treated in a    manner similar to Reference Example 26-(2) to give    2-(2-ethoxyphenyl)thiophene as a pale yellow solid.-   (2) The above 2-(2-ethoxyphenyl)thiophene and    5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1)    were treated in a manner similar to Reference Example 9 to give    5-bromo-2-chloro-1-(5-(2-ethoxyphenyl)-2-thienylmethyl)-benzene as    colorless oil. APCI-Mass m/Z 407/409 (M+H)

REFERENCE EXAMPLE 715-Bromo-2-fluoro-1-(5-phenyl-2-thienylmethyl)benzene

2-Phenylthiophene and 5-bromo-2-fluorobenzaldehyde were treated in amanner similar to Reference Example 7 to give the target compound.APCI-Mass m/Z 347/349 (M+H).

REFERENCE EXAMPLE 725-Bromo-1-(5-(4-ethoxyphenyl)-2-thienylmethyl)-2-fluorobenzene

2-(4-Ethoxyphenyl)thiophene obtained in Reference Example 68—(1) and5-bromo-2-fluorobenzaldehyde were treated in a manner similar toReference Example 7 to give the target compound. APCI-Mass m/Z 391/393(M+H).

REFERENCE EXAMPLE 735-Bromo-1-(5-(2-ethoxyphenyl)-2-thienylmethyl)-2-fluorobenzene

2-(2-Ethoxyphenyl)thiophene obtained in Reference Example 70-(1) and5-bromo-2-fluorobenzaldehyde were treated in a manner similar toReference Example 9 to give the target compound. APCI-Mass m/Z 391/393(M+H).

REFERENCE EXAMPLE 745-Bromo-2-fluoro-1-(5-(2-fluorophenyl)-2-thienylmethyl)-benzene

2-(2-Fluorophenyl)thiophene obtained in Reference Example 66-(1) and5-bromo-2-fluorobenzaldehyde were treated in a manner similar toReference Example 7 to give the target compound. APCI-Mass m/Z 365/367(M+H)

REFERENCE EXAMPLE 755-Bromo-2-chloro-1-(5-(3-fluorophenyl)-2-thienylmethyl)-benzene

-   (1) 2-Iodothiophene and 3-fluorophenylboronic acid were treated in a    manner similar to Reference Example 26-(2) to give    2-(3-fluorophenyl)thiophene as oil.-   (2) The above 2-(3-fluoropheny)thiophene was treated in a manner    similar to Reference Example 5 to give the target compound as    powder.

REFERENCE EXAMPLE 765-Bromo-1-(5-(3-ethoxyphenyl)-2-thienylmethyl)-2-fluorobenzene

2-(3-Ethoxyphenyl)thiophene obtained in Reference Example 69-(1) and5-bromo-2-fluorobenzaldehyde were treated in a manner similar toReference Example 9 to give the target compound. APCI-Mass m/Z 391/393(M+H).

REFERENCE EXAMPLE 775-Bromo-2-fluoro-1-(5-(3-fluorophenyl)-2-thienylmethyl)-benzene

2-(3-Fluorophenyl)thiophene obtained in Reference Example 75-(1) and5-bromo-2-fluorobenzaldehyde were treated in a manner similar toReference Example 7 to give the target compound.

REFERENCE EXAMPLE 785-Bromo-2-fluoro-1-(5-(4-fluorophenyl)-2-thienylmethyl)-benzene

2-(4-Fluorophenyl)thiophene obtained in Reference Example 67-(1) and5-bromo-2-fluorobenzaldehyde were treated in a manner similar toReference Example 7 to give the target compound.

REFERENCE EXAMPLE 795-Bromo-2-methyl-1-(5-phenyl-2-thienylmethyl)benzene

2-Phenylthiophene and 5-bromo-2-methylbenzoic acid obtained in ReferenceExample 4-(1) were treated in a manner similar to Reference Example 5 togive the target compound. APCI-Mass m/Z 343/345 (M+H).

REFERENCE EXAMPLE 805-Bromo-1-(5-(3-fluorophenyl)-2-thienylmethyl)-2-methylbenzene

2-(3-Fluorophenyl)thiophene obtained in Reference Example 75—(1) and5-bromo-2-methylbenzoic acid obtained in Reference Example 4-(1) weretreated in a manner similar to Reference Example 5 to give the targetcompound.

REFERENCE EXAMPLE 815-Bromo-1-(5-(4-fluorophenyl)-2-thienylmethyl)-2-methylbenzene

2-(4-Fluorophenyl)thiophene obtained in Reference Example 67-(1) and5-bromo-2-methylbenzoic acid obtained in Reference Example 4-(1) weretreated in a manner similar to Reference Example 5 to give the targetcompound.

REFERENCE EXAMPLE 825-Bromo-2-methoxy-1-(5-phenyl-2-thienylmethyl)benzene

2-Phenylthiophene was treated in a manner similar to Reference Example 7to give the target compound. APCI-Mass m/Z 359/361 (M+H).

REFERENCE EXAMPLE 835-Bromo-2-methyl-1-(5-(3-methylphenyl)-2-thienylmethyl)-benzene

-   (1) 2-Bromothiophene and 3-methylphenylboronic acid were treated in    a manner similar to Reference Example 26-(2) to give    2-(3-methylphenyl)thiophene as colorless oil.-   (2) The above 2-(3-methylphenyl)thiophene and    5-bromo-2-methylbenzaldehyde obtained in Reference Example 4 were    treated in a manner similar to Reference Example 9 to give the    target compound. APCI-Mass m/Z 357/359 (M+H)

REFERENCE EXAMPLE 845-Bromo-2-chloro-1-(5-(3-methylphenyl)-2-thienylmethyl)-benzene

2-(3-Methylphenyl)thiophene obtained in Reference Example 83-(1) and5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16—(1) weretreated in a manner similar to Reference Example 9 to give the targetcompound. APCI-Mass m/Z 377/379/381 (M+H).

REFERENCE EXAMPLE 855-Bromo-2-chloro-1-(5-(3-chlorophenyl)-2-thienylmethyl)-benzene

-   (1) 2-Bromothiophene and 3-chlorophenylboronic acid were treated in    a manner similar to Reference Example 26-(2) to give    2-(3-chlorophenyl)thiophene as colorless oil.-   (2) The above 2-(3-chlorophenyl)thiophene was treated in a manner    similar to Reference Example 5 to give the target compound as    colorless oil.

REFERENCE EXAMPLE 865-Bromo-1-(5-(3-chlorophenyl)-2-thienylmethyl)-2-methylbenzene

2-(3-Chlorophenyl)thiophene obtained in Reference Example 85-(1) and5-bromo-2-methylbenzoic acid obtained in Reference Example 4-(1) weretreated in a manner similar to Reference Example 5 to give the targetcompound as colorless oil.

REFERENCE EXAMPLE 875-Bromo-1-(5-(3-methoxyphenyl)-2-thienylmethyl)-2-methylbenzene

-   (1) 3-Methoxybromobenzene and thiophene-2-boronic acid were treated    in a manner similar to Reference Example 26-(2) to give    2-(3-methoxyphenyl)thiophene as a yellow liquid. APCI-Mass m/Z 191    (M+H).-   (2) The above 2-(3-methoxyphenyl)thiophene and    5-bromo-2-methylbenzaldehyde obtained in Reference Example 4 were    treated in a manner similar to Reference Example 9 to give the    target compound as yellow oil. APCI-Mass m/Z 373/375 (M+H)

REFERENCE EXAMPLE 884-Bromo-2-(4-ethylphenylmethyl)-2H-isoquinolin-1-one

4-Bromo-2H-isoquiolin-1-one (see EP0355750) was treated in a mannersimilar to Reference Example 2 to give the target compound. APCI-Massm/Z 342/344 (M+H).

REFERENCE EXAMPLE 894-Bromo-2-(4-ethylphenylmethyl)-8-methyl-2H-isoquinolin-1-one

-   (1) To a solution of 8-methyl-2H-isoquiolin-1-one (1.15 g) in    dichloromethane (20 ml) was added dropwise a solution of bromine    (1.26 g) in dichloromethane (4 ml) at room temperature. The mixture    was stirred at the same temperature for one hour, and the solvent    was evaporated under reduced pressure. The residue was crystallized    from ether to give 4-bromo-8-methyl-2H-isoquinolin-1-one (1.86 g) as    colorless crystals. APCI-Mass m/Z 238/240 (M+H).-   (2) The above 4-bromo-8-methyl-2H-isoquinolin-1-one was treated in a    manner similar to Reference Example 2 to give the target compound as    colorless crystals. APCI-Mass m/Z 356/358M+H).

REFERENCE EXAMPLE 90 4-Bromo-2-(4-ethylphenylmethyl)thiophene

-   (1) A solution of 4-bromo-2-thiophenecarboxaldehyde (4.78 g) in    tetrahydrofuran (40 ml) was cooled to 0° C. under argon atmosphere,    and thereto was added dropwise 4-ethylphenylmagnesium bromide (0.5 M    tetrahydrofuran solution, 50 ml). The mixture was stirred at the    same temperature for 30 minutes, and thereto was added a saturated    aqueous ammonium chloride solution, and the mixture was extracted    with ethylacetate. The extract was washed with brine and dried over    magnesium sulfate, and the solvent was evaporated under reduced    pressure. The residue was purified by silica gel column    chromatography (hexane:ethyl acetate=97:3-84:16) to give    4-bromo-2-thienyl-4-ethylphenylmethanol (5.37 g) as colorless oil.    APCI-Mass m/Z 279/281 (M+H—H₂O).-   (2) The above 4-bromo-2-thienyl-4-ethylphenylmethanol was treated in    a manner similar to Reference Example 1-(2) to give the target    compound as colorless oil.

REFERENCE EXAMPLE 91 5-Bromo-2-(4-ethylphenylmethyl)thiophene

5-Bromo-2-thiophenecarboxaldehyde was treated in a manner similar toReference Example 90 to give the target compound. ESI-Mass m/Z 279/281(M−H).

REFERENCE EXAMPLE 92 3-Bromo-2-(4-ethylphenylmethyl)thiophene

-   (1) 2,3-Dibromothiophene and 4-ethylbenzaldehyde were treated in a    manner similar to Reference Example 1-(1) to give    3-bromo-2-thienyl-4-ethylphenylmethanol as yellow oil. APCI-Mass m/Z    279/281 (M+H—H₂O).-   (2) A solution of the above 3-bromo-2-thienyl-4-ethylphenylmethanol    (12.4 g) in diethyl ether (10 ml) was added dropwise into a    suspension of lithium aluminum hydride (2.6 g) and aluminum chloride    (9.0 g) in diethyl ether (35 ml) at 0° C. Subsequently, the mixture    was stirred at room temperature overnight, and then poured onto ice.    The mixture was extracted with diethyl ether, washed with a    saturated aqueous sodium hydrogen carbonate solution, and dried over    magnesium sulfate. The solvent was evaporated under reduced    pressure, and the residue was purified by silica gel column    chromatography (hexane) to give    3-bromo-2-(4-ethylphenylmethyl)thiophene (8.77 g) as colorless oil.    APCI-Mass m/Z 279/281 (M+H).

REFERENCE EXAMPLE 93 5-Bromo-3-(4-ethylphenylmethyl)thiophene

5-Bromo-3-thiophenecarboxaldehyde (see Amishiro, N. et al., Chem. Pharm.Bull. 47 (1999) 1393-1403.) was treated in a manner similar to ReferenceExample 90 to give the target compound.

REFERENCE EXAMPLE 94 5-Bromo-2-chloro-3-(4-ethylphenylmethyl)thiophene

-   (1) 5-Bromo-2-chloro-3-thiophenecarboxylic acid (see Japanese    Unexamined Patent Publication No. 10-324632) was treated in a manner    similar to Reference Example 4-(2) and (3) to give    5-bromo-2-chloro-3-thiophenecarboxaldehyde as pale yellow oil.    APCI-Mass m/Z 239/241/243 (M+H+MeOH—H₂O).-   (2) The above 5-bromo-2-chloro-3-thiophenecarboxaldehyde was treated    in a manner similar to Reference Example 90 to give the target    compound as colorless oil.

REFERENCE EXAMPLE 95 5-Bromo-3-chloro-2-(4-ethylphenylmethyl)thiophene

-   (1) A solution of diisopropylamine (6.8 ml) in tetrahydrofuran    (75 ml) was cooled to −78° C. under argon atmosphere, and thereto    was added dropwise n-butyl lithium (1.59 M hexane solution, 30.5    ml). The reaction mixture was stirred at the same temperature for 30    minutes, and thereto was added dropwise a solution of    3-chloro-2-thiophenecarboxylic acid (3.92 g) in tetrahydrofuran (40    ml). The mixture was stirred at the same temperature for 30 minutes,    and thereto was added dropwise 1,2-dibromo-1,1,2,2-tetrafluoroethane    (6.0 ml). The mixture was stirred at the same temperature for one    hour, and then, warmed to room temperature. The mixture was poured    into a diluted aqueous hydrochloric acid solution, and the solution    was extracted with ethyl acetate. The extract was washed with brine,    and dried over sodium sulfate. The solvent was evaporated under    reduced pressure and the residue was crystallized from a mixed    solvent of diisopropyl ether and hexane to give    5-bromo-3-chloro-2-thiophenecarboxylic acid (3.79 g) as a yellow    solid. ESI-Mass m/Z 239/241 (M−H).-   (2) The above 5-bromo-3-chloro-2-thiophenecarboxylic acid was    treated in a manner similar to Reference Example 94 to give    5-bromo-3-chloro-2-(4-ethylphenylmethyl)thiophene as colorless oil.

REFERENCE EXAMPLE 96 3-Bromo-1-(benzo[b]thiophen-3-ylmethyl)benzene

Thianaphthene-3-carboxaldehyde was treated in a manner similar toReference Example 1 to give the target compound.

REFERENCE EXAMPLE 97 3-Bromo-1-(5-ethyl-2-furylmethyl)benzene

-   (1) 5-Ethyl-2-furaldehyde was treated in a manner similar to    Reference Example 1-(1) to give    3-bromophenyl-5-ethyl-2-furylmethanol as oil. APCI-Mass m/Z 263/265    (M+H—H₂O).-   (2) The above 3-bromophenyl-5-ethyl-2-furylmethanol was treated in a    manner similar to Reference Example 9-(2) to give the target    compound as oil.

REFERENCE EXAMPLE 98 3-Bromo-1-(benzo[b]furan-2-ylmethyl)benzene

2-Benzo[b]furancarboxaldehyde was treated in a manner similar toReference Example 97 to give the target compound.

REFERENCE EXAMPLE 991-(Benzo[b]furan-2-ylmethyl)-5-bromo-2-chlorobenzene

Benzo[b]furan and 5-bromo-2-chlorobenzaldehyde obtained in ReferenceExample 16-(1) were treated in a manner similar to Reference Example 7to give the target compound.

REFERENCE EXAMPLE 1001-(Benzothiazol-2-ylmethyl)-5-bromo-2-methylbenzene

-   (1) Benzothiazole and 5-bromo-2-methylbenzaldehyde obtained in    Reference Example 4 were treated in a manner similar to Reference    Example 7-(1) to give    5-bromo-2-methylphenyl-(benzothiazol-2-yl)methanol as pale yellow    crystals. APCI-Mass m/Z 334/336 (M+H).-   (2) To a solution of the above    5-bromo-2-methylphenyl-(benzothiazol-2-yl)methanol (2.60 g) in    dichloromethane (30 ml)-toluene (10 ml) was added manganese(IV)    oxide (3.42 g), and the mixture was stirred at room temperature for    3 hours. Insoluble materials were filtered off, and the filtrate was    evaporated under reduced pressure to give 5-bromo-2-methylphenyl    benzothiazol-2-yl ketone (2.45 g) as colorless crystals. APCI-Mass    m/Z 332/334 (M+H).-   (3) The above 5-bromo-2-methylphenyl benzothiazol-2-yl ketone was    treated in a manner similar to Reference Example 14-(1) to give    1-(benzothiazol-2-ylmethyl)-5-bromo-2-methylbenzene as oil.    APCI-Mass m/Z 318/320 (M+H)

REFERENCE EXAMPLE 1011-(Benzothiazol-2-ylmethyl)-5-bromo-2-chlorobenzene

Benzothiazole and 5-bromo-2-chlorobenzaldehyde obtained in ReferenceExample 16-(1) were treated in a manner similar to Reference Example 100to give the target compound. APCI-Mass m/Z 338/340 (M+H).

REFERENCE EXAMPLE 1025-Bromo-2-chloro-1-(5-phenyl-2-thiazolylmethyl)benzene

-   (1) A solution of thiazole (10.0 g), iodobenzene (2.63 ml),    tetrakis(triphenylphosphine)palladium (0) (1.36 g) and potassium    acetate (3.46 g) in N,N-dimethylacetamide (100 ml) was stirred under    heating at 100° C. overnight. The solvent was evaporated under    reduced pressure, and added to the residue was ethyl acetate. The    mixture was washed successively with water and brine, and dried over    sodium sulfate. The solvent was evaporated under reduced pressure,    and the residue was purified by silica gel column chromatography    (hexane:ethyl acetate=100:0-90:10) to give 5-phenylthiazole (1.50 g)    as a pale yellow solid. APCI-Mass m/Z 162 (M+H).-   (2) The above 5-phenylthiazole and 5-bromo-2-chlorobenzaldehyde    obtained in Reference Example 16-(1) were treated in a manner    similar to Reference Example 100 to give    5-bromo-2-chloro-1-(5-phenyl-2-thiazolylmethyl)benzene as a yellow    solid. APCI-Mass m/Z 364/366 (M+H).

REFERENCE EXAMPLE 103 3-(4-Ethylphenylmethyl)-2,4-pentanedione

A suspension of sodium iodide (15.0 g) in acetonitrile (100 ml) wascooled to 0° C. under argon atmosphere, and thereto were added dropwisechlorotrimethylsilane (12.7 ml), 2,4-pentanedione (2.05 ml) and4-ethylbenzaldehide (2.68 g), successively. The reaction mixture wasstirred at room temperature for 17 hours, and further stirred at 60° C.for 10 hours. The reaction mixture was cooled to room temperature andpoured into an aqueous sodium thiosulfate solution. The mixture wasextracted with diethyl ether, and the extract was washed with brine anddried over magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography (hexane:ethyl acetate=9:1) to give3-(4-ethylphenylmehyl)-2,4-pentanedione (2.72 g) as pale yellow oil.APCI-Mass m/Z 219 (M+H).

REFERENCE EXAMPLE 104 Tri-n-butyl(4-ethylphenyl)tin

To a solution of magnesium (896 mg) in tetrahydrofuran (20 ml) was addeddibromoethan (0.1 ml), and the mixture was stirred at room temperaturefor 15 minutes. Thereto was added dropwise a solution of1-bromo-4-ethylbenzene (5.7 g) in tetrahydrofuran (20 ml), andsubsequently, the mixture was stirred at room temperature for one hour.The reaction mixture was cooled to −78° C., and thereto was addeddropwise tributyltin chloride (9.49 g). The mixture was stirred at thesame temperature for 30 minutes, and then at room temperature for onehour. To the reaction mixture were added 10% aqueous potassium fluoridesolution and ethyl acetate, and the mixture was stirred at roomtemperature for 30 minutes. Insoluble materials were filtered off. Theorganic layer of the filtrate was washed with water and brinesuccessively, and dried over sodium sulfate. The solvent was evaporatedunder reduced pressure and the residue was purified by alumina columnchromatography (hexane) to give the desiredtri-n-butyl(4-ethylphenyl)tin (10.7 g) as colorless oil. EI-Mass m/Z 337(M-Bu).

REFERENCE EXAMPLE 105 4-(4-Ethylphenylmethyl)pyrazole

-   (1) A mixed solution of 4-ethylbenzyl bromide (10.0 g),    malononitrile (6.64 g), potassium carbonate (6.94 g) and    tetra-n-butylammonium bromide (648 mg) in toluene (100 ml) was    agitated at room temperature for 17 hours. The reaction mixture was    poured into water, and the mixture was extracted with ethyl acetate    twice. The extract was washed successively with water and brine, and    dried over sodium sulfate. The solvent was evaporated under reduced    pressure and the residue was purified by silica gel column    chromatography (hexane:ethyl acetate=6:1) to give    2-(4-ethylphenylmethyl)malononitrile (3.28 g) as a colorless solid.-   (2) A solution of the above 2-(4-ethylphenylmethyl)malononitrile    (1.30 g) and hydrazine hydrate (0.86 ml) in ethanol (35 ml) was    heated under reflux for 4 hours. Hydrazine hydrate (0.43 ml) was    further added thereto and the mixture was further heated under    reflux for 4 hours. The reaction mixture was cooled to room    temperature and the solvent was evaporated under reduced pressure.    The residue was crystallized from ethyl acetate-diethyl ether to    give 3,5-diamino-4-(4-ethylphenylmethyl)pyrazole (2.63 g) as pale    pink powder. APCI-Mass m/Z 217 (M+H).-   (3) The above 3,5-diamino-4-(4-ethylphenylmethyl)pyrazole (1.30 g)    was added to 50% aqueous phosphoric acid solution (19 ml), and    further added thereto was water (10 ml). The mixture was cooled to    0° C., and thereto was added dropwise an aqueous solution (4 ml) of    sodium nitrite (912 mg). The mixture was stirred at the same    temperature for 30 minutes, and further stirred at room temperature    for 4 hours. The reaction mixture was cooled again to 0° C., 10%    aqueous sodium hydroxide solution was added thereto to adjust pH of    the reaction mixture to 7. The mixture was extracted with ethyl    acetate, washed successively with water and brine, and dried over    magnesium sulfate. The solvent was evaporated under reduced    pressure, and the residue was purified by silica gel column    chromatography (chloroform:methanol=100:0-90:10) to give the desired    4-(4-ethylphenylmethyl)pyrazole (414 mg) as a pale brown semisolid.    APCI-Mass m/Z 187 (M+H).

REFERENCE EXAMPLE 106 3-(4-Ethylphenylmethyl)-5-methyl-1H-pyrazole

-   (1) 4-Ethylphenylacetic acid (3.0 g) (see Japanese Unexamined Patent    Publication 63-233975) was dissolved in dichloromethane (15 ml), and    thereto were added oxalyl chloride (6.0 ml) and    N,N-dimethylformamide (one drop). The mixture was stirred at room    temperature for 1.5 hours. The reaction mixture was evaporated under    reduced pressure, and the residue was subjected to azeotropic    distillation with toluene to give a crude 4-ethylphenylacetyl    chloride, which was used in the subsequent step without further    purification.-   (2) A suspension of magnesium chloride (1.74 g) in dichloromethane    (30 ml) was cooled to 0° C., and thereto were added t-butyl    acetoacetate (3.03 ml) and pyridine (2.96 ml), and successively was    added a solution of the above 4-ethylphenylacetyl chloride in    dichloromethane (30 ml). The mixture was stirred at the same    temperature for 2.5 hours, and an aqueous citric acid solution was    added thereto. The mixture was extracted with chloroform. The    extract was washed with brine, and dried over sodium sulfate. The    solvent was evaporated under reduced pressure. The residue was    purified by silica gel column chromatography (hexane:ethyl    acetate=15:1) to give t-butyl    2-acetyl-4-(4-ethylphenyl)-3-oxobutyrate (4.75 g) as pale yellow    oil. APCI-Mass m/Z 322 (M+NH₄)-   (3) A solution of the above t-butyl    2-acetyl-4-(4-ethylphenyl)-3-oxobutyrate in trifluoroacetic acid    (60 ml) was stirred at room temperature for 2 hours. The solvent was    evaporated under reduced pressure, and the residue was dissolved in    ethyl acetate, and the mixture was washed successively with a    saturated aqueous sodium hydrogen carbonate solution and brine. The    mixture was dried over sodium sulfate, and the solvent was    evaporated under reduced pressure to give    1-(4-ethylphenyl)-4-hydroxy-3-penten-2-one (4.00 g) as yellow oil.    APCI-Mass m/Z 205 (M+H).-   (4) A solution of the above    1-(4-ethylphenyl)-4-hydroxy-3-penten-2-one (3.98 g) and hydrazine    hydrate (4.0 ml) in toluene (20 ml) was stirred under heating at    100° C. for 1.5 hours. The reaction mixture was cooled to room    temperature, and washed successively with water and brine, and dried    over sodium sulfate. The solvent was evaporated under reduced    pressure. The residue was purified by silica gel column    chromatography (chloroform:ethyl acetate=2:1) to give    3-(4-ethylphenylmethyl)-5-methyl-1H-pyrazole (3.12 g) as yellow oil.    APCI-Mass m/Z 201 (M+H).

REFERENCE EXAMPLE 107 3-(4-Ethylphenylmethyl)-6-hydroxypyridine

-   (1) To a solution of 6-chloronicotinoyl chloride (10.0 g) and    N,O-dimethylhydroxyamine hydrochloride (6.65 g) in dichloromethane    (200 ml) was added dropwise triethylamine (17.2 g) at 0° C.    Subsequently the mixture was stirred at room temperature overnight.    The mixture was washed successively with water, 5% aqueous citric    acid solution, water and brine, and then, dried over sodium sulfate.    The solvent was evaporated under reduced pressure to give    N-methoxy-N-methyl-6-chloronicotinamide (11.73 g) as pale yellow    oil. APCI-Mass m/Z 201/203 (M+H).-   (2) A solution of the N-methoxy-N-methyl-6-chloronicotineamide    (4.2 g) in tetrahydrofuran (40 ml) was cooled to 0° C., and thereto    was added dropwise 4-ethylphenylmagnesium bromide (0.5 M    tetrahydrofuran solution, 55 ml). The mixture was stirred at 0° C.    for 4 hours, and then at the room temperature for 10 minutes. The    reaction mixture was cooled again to 0° C., and added thereto was    10% aqueous hydrochloric acid solution. The mixture was extracted    with ethyl acetate, and washed with brine and dried over sodium    sulfate. The solvent was evaporated under reduced pressure, and the    residue was purified by silica gel column chromatography    (hexane:ethyl acetate=20:1) to give 6-chloro-3-pyridyl 4-ethylphenyl    ketone (3.68 g) as colorless crystals. APCI-Mass m/Z 246/248 (M+H).-   (3) The above 6-chloro-3-pyridyl 4-ethylphenyl ketone (1.68 g) was    dissolved in N-methyl-2-pyrrolidinone (20 ml), and thereto were    added benzylalcohol (815 ml) and 60% sodium hydride (275 mg). The    mixture was stirred at room temperature for 6 hours, and then at    90° C. for one hour. The reaction mixture was cooled to room    temperature, and water was added thereto, and the mixture was    extracted with ethyl acetate. The extract was washed with water and    subsequently with brine, and dried over sodium sulfate. The solvent    was evaporated under reduced pressure, and the residue was purified    by silica gel column chromatography (hexane:ethyl    acetate=100:0-95:5) to give 6-benzyloxy-3-pyridyl 4-ethylphenyl    ketone (1.68 g) as colorless oil. APCI-Mass m/Z 318 (M+H).-   (4) The above 6-benzyloxy-3-pyridyl 4-ethylphenyl ketone (865 mg)    was dissolved in ethylene glycol (8.5 ml), and thereto were added    hydrazine hydrate (0.44 ml) and potassium hydroxide (550 mg). The    mixture was stirred under heating at 190° C. for 8 hours. The    reaction mixture was cooled to room temperature, and water was added    thereto, and the mixture was extracted with ethyl acetate. The    extract was washed with water three times, and subsequently with    brine, and dried over sodium sulfate. The solvent was evaporated    under reduced pressure, and the residue was purified by silica gel    column chromatography (hexane:ethyl acetate=100:0-0:100) to give the    desired 3-(4-ethylphenylmethyl)-6-hydoroxypyridine (256 mg) as    colorless powder. APCI-Mass m/Z 214 (M+H).

REFERENCE EXAMPLE 108 3-(4-Ethylphenylmethyl)-2-hydroxypyridine

-   (1) 2-Chloronicotinoyl chloride was treated in a manner similar to    Reference Example 107-(1), (2) and (3) to give 2-benzyloxy-3-pyridyl    4-ethylphenyl ketone as colorless oil. APCI-Mass m/Z 318 (M+H).-   (2) The above 2-benzyloxy-3-pyridyl 4-ethylphenyl ketone (1.69 g)    was dissolved in ethanol (15 ml), and thereto was added sodium    borohydride (403 mg), and the mixture was stirred at room    temperature for 3 hours. The solvent was evaporated under reduced    pressure, and the residue was dissolved in ethyl acetate. The    mixture was washed with water and successively with brine, and dried    over sodium sulfate. The solvent was evaporated under reduced    pressure to give crude 2-benzyloxy-3-pyridyl-4-ethylphenylmethanol    as colorless oil, which was used in the subsequent step without    further purification.-   (3) The above 2-benzyloxy-3-pyridyl-4-ethylphenylmethanol was    dissolved in methanol (10 ml), and thereto were added concentrated    hydrochloric acid (1.0 ml) and 10% palladium-carbon (500 mg). The    mixture was stirred at room temperature for 15 hours under hydrogen    atmosphere under normal pressure. Insoluble materials were filtered    off, and the solvent was evaporated under reduced pressure. The    residue was dissolved in ethyl acetate, and the solution was washed    with water and successively with brine, and dried over sodium    sulfate. The solvent was evaporated under reduced pressure, and the    residue was purified by silica gel column chromatography    (chloroform:methanol=100:0-97:3) to give the desired    3-(4-ethylphenylmethyl)-2-hydoroxypyridine (307 mg) as a pale brown    solid. APCI-Mass m/Z 214 (M+H).

REFERENCE EXAMPLE 109 3-(4-Ethylphenylmethyl)-1H-indole

-   (1) To a solution of indole (6.00 g) in methanol (60 ml) were added    sodium hydroxide (2.25 g) and 4-ethylbenzaldehyde (7.56 g), and the    mixture was stirred at room temperature for 3 days under argon    atmosphere. Added thereto was water, and methanol was evaporated    under reduced pressure. The residue was extracted with diethyl    ether, and the extract was washed with water, and dried over    magnesium sulfate. The solvent was evaporated under reduced pressure    and the residue was purified by silica gel column chromatography    (hexane:ethyl acetate=98:2-70:30) to give    4-ethylphenyl-(1H-indol-3-yl)methanol (2.10 g) as a colorless solid.    APCI-Mass m/Z 234 (M+H—H₂O).-   (2) The above 4-ethylphenyl-(1H-indol-3-yl)methanol was treated in a    manner similar to Reference Example 1-(2) to give the desired    3-(4-ethylphenylmethyl)-1H-indole as colorless crystals. APCI-Mass    m/Z 236 (M+H).

REFERENCE EXAMPLE 110 3-(4-Ethylphenylmethyl)-1H-indazole

-   (1) A mixture of zinc powder (712 mg) and dibromoethane (0.04 ml) in    N,N-dimethylformamide (2.5 ml) were stirred under heating at 70° C.    for 10 minutes under argon atmosphere. The reaction mixture was    cooled to room temperature, and chlorotrimethylsilane (0.04 ml) was    added thereto, and the mixture was stirred at room temperature for    30 minutes. To the activated zinc solution was added dropwise a    solution of 4-ethylbenzyl bromide (1.74 g) in N,N-dimethylformamide    (10 ml) at 0° C. over a period of 2 hours. Subsequently, the mixture    was stirred at 0° C. for 2 hours, to prepare a solution of    4-ethylbenzylzinc bromide in N,N-dimethylformamide, which was used    in the subsequent step without further purification.-   (2) A solution of tris(dibenzylideneacetone)dipalladium (0) (167 mg)    and tri(2-furyl)phosphine (135 mg) in tetrahydrofuran (20 ml) was    stirred at room temperature for 5 minutes under argon atmosphere.    Thereto were added 1-t-butoxycarbonyl-3-iodo-1H-indazole (2.0 g) and    the above 4-ethylbenzylzinc bromide (N,N-dimethylformamide solution)    at 0° C., and the mixture was stirred at room temperature for 5    hours. The reaction mixture was poured into water, and the mixture    was extracted with diethyl ether. The extract was washed with water    and dried over magnesium sulfate. The solvent was evaporated under    reduced pressure, and the residue was purified by silica gel column    chromatography (hexane:ethyl acetate=100:0-92:8) to give    1-t-butoxycarbonyl-3-(4-ethylphenylmethyl)-1H-indazole (1.37 g) as    colorless oil. APCI-Mass m/Z 337 (M+H).-   (3) The above 1-t-butoxycarbonyl-3-(4-ethylphenylmethyl)-1H-indazole    (1.35 g) was dissolved in methanol (15 ml), and added thereto was    28% sodium methoxide solution (methanol solution, 1.0 ml), and the    mixture was stirred at room temperature for one hour. Added thereto    was an aqueous citric acid solution, and the mixture was extracted    with ethyl acetate. The extract was washed successively with water    and brine, and dried over magnesium sulfate. The solvent was    evaporated under reduced pressure, and the residue was crystallized    from hexane to give the desired 3-(4-ethylphenylmethyl)-1H-indazole    (800 mg) as colorless crystals. APCI-Mass m/Z 237 (M+H).

REFERENCE EXAMPLE 1115-Bromo-2-methyl-1-(5-(4-trifluoromethylphenyl)-2-thienylmethyl)benzene

-   (1) 4-Bromobenzotrifluoride and thiophene-2-boronic acid were    treated in a manner similar to Reference Example 20-(1) to give    2-(4-trifluoromethylphenyl)thiophene as colorless crystals.-   (2) The above 2-(4-trifluoromethylphenyl)thiophene and    5-bromo-2-methylbenzaldehyde obtained in Reference Example 4 were    treated in a manner similar to Reference Example 7 to give the    desired    5-bromo-2-methyl-1-(5-(4-trifluoromethylphenyl)-2-thienyl-methyl)benzene    as colorless crystals. APCI-Mass m/Z 425/427 (M+H+MeOH).

REFERENCE EXAMPLE 1125-Bromo-2-methyl-1-(5-(3-trifluoromethylphenyl)-2-thienylmethyl)benzene

-   (1) 3-Bromobenzotrifluoride and thiophene-2-boronic acid were    treated in a manner similar to Reference Example 20-(1) to give    2-(3-trifluoromethylphenyl)thiophene as colorless oil.-   (2) The above 2-(3-trifluoromethylphenyl)thiophene and    5-bromo-2-methylbenzaldehyde obtained in Reference Example 4 were    treated in a manner similar to Reference Example 7 to give the    desired    5-bromo-2-methyl-1-(5-(3-trifluoromethylphenyl)-2-thienyl-methyl)benzene    as colorless oil.

REFERENCE EXAMPLE 113 2-(4-Ethylphenyl)thiophene

2-Bromothiophene and 4-ethylphenylboronic acid were treated in a mannersimilar to Reference Example 20-(1) to give the target compound.

REFERENCE EXAMPLE 114 2-(4-Methylphenyl)thiophene

2-Bromothiophene and 4-methylphenylboronic acid were treated in a mannersimilar to Reference Example 20-(1) to give the target compound.

REFERENCE EXAMPLE 115 2-(2,3-Dihydro-5-benzo[b]furanyl)thiophene

-   (1) 5,7-Dibromo-2,3-dihydrobenzo[b]furan (see WO 02/070020) (3.0 g)    in diethyl ether was cooled to −78° C. under argon atmosphere, and    thereto was added dropwise n-butyl lithium (2.44 M hexane solution,    5.09 ml). The mixture was stirred at the same temperature for 30    minutes, and poured into a saturated aqueous ammonium chloride    solution. The mixture was extracted with diethyl ether, and dried    over magnesium sulfate. The solvent was evaporated under reduced    pressure to give 5-bromo-2,3-dihydrobenzo[b]furan (2.0 g) as pale    yellow crystals, which was used in the subsequent step without    further purification.-   (2) The above 5-bromo-2,3-dihydrobenzo[b]furan and    thiophene-2-boronic acid were treated in a manner similar to    Reference Example 20-(1) to give the desired    2-(2,3-dihydro-5-benzo[b]furanyl)thiophene as pale yellow crystals.    APCI-Mass m/Z 203 (M+H).

REFERENCE EXAMPLE 1164-Bromo-2-(5-chloro-2-thienylmethyl)-1-fluoronaphthalene

-   (1) A solution of 2,2,6,6-tetramethylpiperidine (1.04 g) in    tetrahydrofuran (15 ml) was cooled to −78° C. under argon    atmosphere, and thereto was added dropwise n-butyl lithium (1.58 M    hexane solution, 4.43 ml). The reaction mixture was stirred at the    same temperature for 30 minutes, and thereto was added dropwise a    solution of 1-bromo-4-fluoronaphthalene (1.50 g) in tetrahydrofuran    (12 ml) at −78° C. The mixture was stirred at the same temperature    for one hour, and thereto was added dropwise a solution of    5-chloro-2-thiophenecarboxaldehyde (1.07 g) in tetrahydrofuran    (11 ml) at −78° C. The mixture was stirred at the same temperature    for 30 minutes, and thereto was added a saturated aqueous ammonium    chloride solution, and the reaction mixture was extracted with ethyl    acetate. The extract was washed with brine, dried over sodium    sulfate, and the solvent was evaporated under reduced pressure. The    residue was purified by an aminosilane-treated silica gel column    chromatography (hexane:ethyl acetate=3:1) to give    4-bromo-1-fluoro-2-naphthyl-5-chloro-2-thienylmethanol (2.00 g) as    pale yellow powder. APCI-Mass m/Z 353/355 (M+H—H₂O).-   (2) The above 4-bromo-1-fluoro-2-naphthyl-5-chloro-2-thienylmethanol    was treated in a manner similar to Reference Example 1-(2) to give    the desired 4-bromo-2-(5-chloro-2-thienylmethyl)-1-fluoronaphthalene    as a yellow solid.

REFERENCE EXAMPLE 1175-Bromo-2,4-dimethyl-1-(5-phenyl-2-thienylmethyl)benzene

-   (1) 2,4-dimethylbenzoic acid (20.0 g) was suspended in chloroform    (100 ml), and thereto were added oxalyl chloride (6.8 ml) and    N,N-dimethylformamide (2 drops). The mixture was stirred at room    temperature overnight. The solvent was evaporated under reduced    pressure, and the residue was dissolved in methanol (200 ml). The    mixture was stirred at room temperature for 3 hours. The solvent was    evaporated under reduced pressure, and the residue was dissolved in    ethyl acetate. The mixture was washed successively with a saturated    aqueous sodium hydrogen carbonate solution and brine, and dried over    sodium sulfate. The solvent was evaporated under reduced pressure to    give methyl 2,4-dimethylbenzoate as pale yellow oil, which was used    in the subsequent step without further purification.-   (2) To a mixture of the above methyl 2,4-dimethylbenzoate (19.75 g)    and activated aluminum neutral oxide (120 g) was added dropwise    bromine (9.25 ml) while stirring at room temperature. The mixture    was stirred at room temperature for 8 hours, and diluted with    diethyl ether (1000 ml). Insoluble materials were filtered off, and    washed with diethyl ether (500 ml). The combined filtrate was washed    successively with 10% aqueous sodium thiosulfate solution, a    saturated aqueous sodium hydrogen carbonate solution and brine. The    filtrate was dried over magnesium sulfate, and the solvent was    evaporated under reduced pressure. The residue was crystallized from    methanol (40 ml) to give methyl 5-bromo-2,4-dimethylbenzoate    (6.34 g) as colorless crystals. APCI-Mass m/Z 243/245 (M+H).-   (3) The above methyl 5-bromo-2,4-dimethylbenzoate was treated in a    manner similar to Reference Example 4-(1) to give    5-bromo-2,4-dimethylbenzoic acid as colorless crystals. ESI-Mass m/Z    227/229 (M−H).-   (4) The above 5-bromo-2,4-dimethylbenzoic acid and 2-phenylthiophene    were treated in a manner similar to Reference Example 5 to give    5-bromo-2,4-dimethyl-1-(5-phenyl-2-thienylmethyl)benzene as    colorless crystals. APCI-Mass m/Z 357/359 (M+H).

REFERENCE EXAMPLE 1185-Bromo-1-(5-phenyl-2-thienylmethyl)-2-trifluoromethyl-benzene

-   (1) 5-Bromo-2-iodobenzoic acid (see Jorg Frahn, A.-Dieter Schluter    Synthesis 1997, 1301-1304) was treated in a manner similar to    Reference Example 117-(1) to give methyl 5-bromo-2-iodobenzoate as a    brown solid.-   (2) To a solution of the above methyl 5-bromo-2-iodobenzoate    (4.65 g) in N-methyl-2-pyrrolydinone (20 ml) were added copper (I)    bromide (235 mg) and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate    (2.6 ml), and the mixture was stirred under heating at 120° C. for    1.5 hours. The reaction mixture was cooled, and added thereto were    10% aqueous hydrochloric acid solution and ethyl acetate. Insoluble    materials were filtered off, and an organic layer of the filtrate    was washed with water for 4 times, and subsequently washed with a    saturated aqueous sodium hydrogen carbonate solution and brine. The    filtrate was dried over sodium sulfate, and the solvent was    evaporated under reduced pressure. The residue was purified by    silica gel column chromatography (hexan:ethyl acetate=80:1) to give    methyl 5-bromo-2-trifluoromethylbenzoate (3.55 g) as colorless oil.-   (3) The above methyl 5-bromo-2-trifluoromethylbenzoate was treated    in a manner similar to Reference Example 4-(1) to give    5-bromo-2-trifluoromethylbenzoic acid as pale brown crystals.    ESI-Mass m/Z 267/269 (M−H).-   (4) The above 5-bromo-2-trifluoromethylbenzoic acid and    2-phenylthiophene were treated in a manner similar to Reference    Example 5-(1) to give 5-bromo-2-trifluoromethylphenyl    5-phenyl-2-thienyl ketone as pale yellow crystals. APCI-Mass m/Z    411/413 (M+H).-   (5) To a mixed solution of the above 5-bromo-2-trifluoromethylphenyl    5-phenyl-2-thienyl ketone (670 mg) in methanol (20    ml)-tetrahydrofuran (10 ml) was added sodium borohydride (62 mg),    and the mixture was stirred at room temperature for 3 hours. The    solvent was evaporated under reduced pressure, and the residue was    dissolved in chloroform (10 ml)-acetonitrile (20 ml). Thereto was    added triethylsilane (0.78 ml), and the mixture was cooled to 0° C.    Thereto was added dropwise boron trifluoride.diethyl ether complex    (0.52 ml). The mixture was stirred at room temperature for 45    minutes, and added thereto was a saturated aqueous sodium hydrogen    carbonate solution, and the mixture was extracted with ethyl    acetate. The extract was washed with brine, and dried over sodium    sulfate. The solvent was evaporated under reduced pressure, and the    residue was purified by silica gel column chromatography (hexane) to    give the desired    5-bromo-1-(5-phenyl-2-thienylmethyl)-2-trifluoromethylbenzene (565    mg) as colorless oil.

REFERENCE EXAMPLE 1195-Bromo-1-(5-(3-ethylphenyl)-2-thienylmethyl)-2-methyl-benzene

-   (1) 1-Bromo-3-ethylbenzene and thiophene-2-boronic acid were treated    in a manner similar to Reference Example 20-(1) to give    2-(3-ethylphenyl)thiophene as a pale yellow liquid.-   (2) The above 2-(3-ethylphenyl)thiophene and    5-bromo-2-methylbenzaldehyde obtained in Reference Example 4 were    treated in a manner similar to Reference Example 9 to give    5-bromo-1-(5-(3-ethylphenyl)-2-thienylmethyl)-2-methyl-benzene as    pale yellow oil. APCI-Mass m/Z 371/373 (M+H).

REFERENCE EXAMPLE 1205-Bromo-2-methyl-1-(5-(2-pyridyl)-2-thienylmethyl)benzene

-   (1) 2-(2-Pyridyl)thiophene and 5-bromo-2-mehtylbenzaldehyde obtained    in Reference Example 4 were treated in a manner similar to Reference    Example 7-(1) to give    5-bromo-2-methylphenyl-5-(2-pyridyl)-2-thienylmethanol as colorless    oil. APCI-Mass m/Z 360/362 (M+H).-   (2) A solution of the above    5-bromo-2-methylphenyl-5-(2-pyridyl)-2-thienylmethanol (1.59 g) in    trifluoroacetic acid (40 ml) was cooled to 0° C., and thereto were    added gradually sodium triacetoxyborohydride (4.68 g). The mixture    was stirred at room temperature for one hour, and cooled again to    0° C. 10% aqueous sodium hydroxide solution was added thereto to    basify the reaction mixture. The mixture was extracted with ethyl    acetate, and the extract was washed with brine, and dried over    sodium sulfate. The solvent was evaporated under reduced pressure    and the residue was purified by silica gel column chromatography    (hexane:ethyl acetate=3:1) to give the desired    5-bromo-2-methyl-1-(5-(2-pyridyl)-2-thienylmethyl)benzene (1.38 g)    as a colorless solid. APCI-Mass m/Z 344/346 (M+H).

REFERENCE EXAMPLE 121 2-(5-Fluoro-2-thienyl)thiophene

2,2′-Bithiophene (7.40 g) in tetrahydrofuran (90 ml) was cooled to −78°C. under argon atmosphere, and thereto were added dropwise n-butyllithium (1.59 M hexane solution, 28.0 ml). The mixture was stirred at 0°C. for one 30 minutes, and cooled again to −78° C. Added thereto wasN-fluorobenzenesulfonimide (15.5 g), and the mixture was graduallywarmed, and stirred at room temperature for 17 hours. The reactionmixture was poured into ice-cold water, and the solution was extractedwith hexane twice, and the extract was washed successively with waterand brine, and dried over sodium sulfate. The solvent was evaporatedunder reduced pressure and the residue was purified by silica gel columnchromatography (hexane) to give 2-(5-fluoro-2-thienyl)thiophene (5.89 g)as colorless oil.

REFERENCE EXAMPLE 1225-Bromo-2-methyl-1-(5-(3-pyridyl)-2-thienylmethyl)benzene

2-(3-Pyridyl)thiophene was treated in a manner similar to ReferenceExample 120 to give the target compound as colorless crystals. APCI-Massm/Z 344/346 (M+H).

REFERENCE EXAMPLE 1235-Bromo-1-(5-(4-methoxyphenyl)-2-thienylmethyl)-2-methylbenzene

-   (1) p-Bromoanisole and thiophene-2-boronic acid were treated in a    manner similar to Reference Example 20-(1) to give    2-(4-methoxyphenyl)thiophene as a pale yellow solid. APCI-Mass m/Z    191 (M+H).-   (2) The above 2-(4-methoxyphenyl)thiophene and    4-bromo-2-methylbenzoic acid obtained in Reference Example 4-(1)    were treated in a manner similar to Reference Example 5 to give    5-bromo-1-(5-(4-methoxyphenyl)-2-thienylmethyl)-2-methyl-benzene as    a pale yellow solid. APCI-Mass m/Z 373/375 (M+H).

REFERENCE EXAMPLE 1245-bromo-2-methyl-1-(5-(1,2-Methylenedioxybenzen-4-yl)-2-thienylmethyl)benzene

4-Bromo-1,2-(methylenedioxy)benzene was treated in a manner similar toReference Example 119 to give the target compound as colorless powder.

REFERENCE EXAMPLE 1255-Bromo-2-chloro-1-(2-(5-phenyl-2-thienyl)ethyl)benzene

-   (1) To a solution of 5-bromo-2-chlorobenzyl alcohol (10.66 g) in    toluene (100 ml) solution were added thionyl chloride (10 ml), and    pyridine (2 drops), and the mixture was stirred under heating at    100° C. overnight. The solvent was evaporated under reduced    pressure, and the residue was dissolved in ethyl acetate. The    solution was washed successively with water, a 10% aqueous    hydrochloric acid solution, a saturated aqueous sodium hydrogen    carbonate solution and brine, and dried over sodium sulfate. The    solvent was evaporated under reduced pressure to give    5-bromo-2-chlorobenzyl chloride as pale yellow crystals, which was    used in the subsequent step without further purification.-   (2) The above 5-bromo-2-chlorobenzyl chloride was dissolved in    acetonitrile (100 ml), and the mixture was cooled to 0° C. Added    thereto was tetraethylammonium cyanide (8.8 g), and the mixture was    stirred at room temperature for 2 hours. The solvent was evaporated    under reduced pressure, and the residue was dissolved in ethyl    acetate. The solution was washed successively with water, 10%    aqueous hydrochloric acid solution, a saturated aqueous sodium    hydrogen carbonate solution and brine, and dried over sodium    sulfate. The solvent was evaporated under reduced pressure to give    5-bromo-2-chlorophenylacetonitrile as a pale yellow solid, which was    used in the subsequent step without further purification.-   (3) The above 5-bromo-2-chlorophenylacetonitrile was added to water    (90 ml)-sulfuric acid (75 ml), and the mixture was stirred under    heating at 160° C. overnight. The mixture was further diluted with    water, and cooled to 0° C. The solvent was removed by decant, and    the residue was dissolved in diethyl ether. The solution was washed    with water and brine, and extracted with 10% sodium hydroxide. To    the extract was added concentrated hydrochloric acid to make the    solution acidic. The precipitates were collected by filtration, and    purified by silica gel column chromatography (chloroform) to give    5-bromo-2-chlorophenylacetic acid (6.67 g) as colorless crystals.    ESI-Mass m/Z 247/249 (M−H).-   (4) The above 5-bromo-2-chlorophenylacetic acid was treated in a    manner similar to Reference Example 118-(4) and (5) to give the    desired 5-bromo-2-chloro-1-(2-(5-phenyl-2-thienyl)ethyl)benzene as a    pale yellow solid. APCI-Mass m/Z 377/379 (M+H).

REFERENCE EXAMPLE 1265-Bromo-1-(5-(6-fluoro-2-pyridyl)-2-thienylmethyl)2-methylbenzene

-   (1) 2-Bromo-6-fluoropyridine and thiophene-2-boronic acid were    treated in a manner similar to Reference Example 20-(1) to give    2-(6-fluoro-2-pyridyl)thiophene as yellow oil. APCI-Mass m/Z 180    (M+H).-   (2) The above 2-(6-fluoro-2-pyridyl)thiophene was treated in a    manner similar to Reference Example 120 to give the desired    5-bromo-1-(5-(6-fluoro-2-pyridyl)-2-thienylmethyl)2-methyl-benzene    as a colorless solid. APCI-Mass m/Z 362/364 (M+H).

REFERENCE EXAMPLE 1275-Bromo-2-methyl-1-(5-trifluoromethyl-2-thienylmethyl)-benzene

2-Trifluoromethylthiophene (see Japanese Unexamined Patent PublicationNo. 2000-34239) and 5-bromo-2-methylbenzaldehyde obtained in ReferenceExample 4 were treated in a manner similar to Reference Example 7 togive the target compound as colorless oil.

REFERENCE EXAMPLE 1285-Bromo-1-(5-(5-fluoro-2-thienyl)-2-thienylmethyl)-2-methyl benzene

5-Bromo-2-methylbenzoic acid obtained in Reference Example 4-(1) and2-(5-fluoro-2-thienyl)thiophene obtained in Reference Example 121 weretreated in a manner similar to Reference Example 5 to give the targetcompound as a colorless solid. APCI-Mass m/Z 367/369 (M+H).

REFERENCE EXAMPLE 1293-Bromo-2-fluoro-6-methyl-1-(5-phenyl-2-thienylmethyl)-benzene

4-Bromo-3-fluorotoluene and 5-phenyl-2-thiophenecarboxaldehyde weretreated in a manner similar to Reference Example 116 to give the targetcompound as pale blue powders. APCI-Mass m/Z 361/363 (M+H).

REFERENCE EXAMPLE 1305-Bromo-2-chloro-1-(2-phenyl-5-thiazolylmethyl)benzene

-   (1) 5-Bromo-2-chlorophenylacetic acid (2.0 g) obtained in Reference    Example 125-(3) was dissolved in dichloromethane (40 ml), and    thereto were added oxalyl chloride (0.77 ml) and    N,N-dimethylformamide (one drop) at 0° C. The mixture was stirred at    room temperature overnight. The solvent was evaporated under reduced    pressure to give 5-bromo-2-chlorophenylacetyl chloride, which was    used in the subsequent step without further purification.-   (2) A solution of potassium t-butoxide (1.35 g) in tetrahydrofuran    (20 ml) was cooled to 0° C., and thereto was added methyl    isocyanoacetate (1.33 ml). Then, a solution of the above    5-bromo-2-chlorophenylacetyl chloride in tetrahydrofuran (20 ml) was    added thereto, and the mixture was stirred at 0° C. for 2 hours, and    then at room temperature overnight. The mixture was cooled again to    0° C. 10% aqueous citric acid solution was added thereto, and the    mixture was extracted with ethyl acetate. The extract was washed    with water and brine, and dried over sodium sulfate. The solvent was    evaporated under reduced pressure and the residue was purified by    silica gel column chromatography (hexane:ethyl acetate=3:1) to give    5-bromo-2-chloro-1-(4-methoxycarbonyl-5-oxazolylmethyl)-benzene    (1.12 g) as a yellow solid. APCI-Mass m/Z 330/332 (M+H).-   (3) The above    5-bromo-2-chloro-1-(4-methoxycarbonyl-5-oxazolylmethyl)-benzene    (1.37 g) was heated under reflux in 6N aqueous hydrochloric acid    solution (20 ml) overnight. The solvent was evaporated under reduced    pressure, and the residue was dissolved in methanol, and treated    with carbon powder. The carbon powder was filtered off, and the    filtrate was evaporated under reduced pressure to give crude    1-(3-amino-2-oxopropyl)-5-bromo-2-chlorobenzene-hydro-chloride    (1.73 g) as a pale brown solid, which was used in the subsequent    step without further purification. APCI-Mass m/Z 262/264 (M+H).-   (4) A mixed solution of the above    1-(3-amino-2-oxopropyl)-5-bromo-2-chlorobenzene-hydro-chloride    (1.70 g) in ethyl acetate (30 ml)-water (15 ml) was cooled to 0° C.    Added thereto were benzoyl chloride (0.99 ml) and sodium hydrogen    carbonate (2.39 g), and the mixture was stirred at the same    temperature for 3 hours. The organic layer was washed with brine,    and dried over sodium sulfate. The solvent was evaporated under    reduced pressure and the residue was purified by silica gel column    chromatography (chloroform:ethyl acetate=95:5) to give    1-(3-benzoylamino-2-oxopropyl)-5-bromo-2-chlorobenzene (710 mg) as a    colorless solid. APCI-Mass m/Z 366/368 (M+H).-   (5) To a solution of the above    1-(3-benzoylamino-2-oxopropyl)-5-bromo-2-chlorobenzene (710 mg) in    toluene (20 ml) was added Lawesson reagent (2.35 g), and the mixture    was heated under reflux for 2 hours. The reaction mixture was    cooled, and the solvent was evaporated under reduced pressure. The    residue was purified by silica gel column chromatography    (hexane:ethyl acetate=90:10) to give the desired    5-bromo-2-chloro-1-(2-phenyl-5-thiazolylmethyl)benzene (512 mg) as a    colorless solid. APCI-Mass m/Z 364/366 (M+H).

REFERENCE EXAMPLE 131 t-Butyl 5-bromo-2-chlorobenzoic acid

To a solution of 5-bromo-2-chlorobenzoic acid (11.75 g) inN,N-dimethylformamide (50 ml) was added 1,1′-carbonyldiimidazole (8.10g), and the mixture was stirred under heating at 40° C. for one hour.Thereto were added t-butanol (7.40 g) and1,8-diazabicyclo[5.4.0]undec-7-ene (7.60 g), and the mixture was furtherstirred under heating at 40° C. overnight. The mixture was diluted withdiethyl ether, and washed successively with water (3 times), 2% aqueoushydrochloric acid solution (twice), a saturated aqueous sodium hydrogencarbonate solution and brine. The mixture was dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure to givet-butyl 5-bromo-2-chlorobenzoate (12.53 g) as pale yellow oil.

REFERENCE EXAMPLE 1325-Bromo-2-chloro-1-(6-ethoxybenzo[b]thiophen-2-ylmethyl)benzene

-   (1) A solution of    5-bromo-2-chloro-1-(6-methoxybenzo[b]thiophen-2-ylmethyl)benzene    (2.70 g) obtained in Reference Example 46 in dichloromethane (27 ml)    was cooled to 0° C. under argon atmosphere, and thereto was added    dropwise boron tribromide (0.83 ml). The mixture was warmed to room    temperature, and stirred for 30 minutes. The mixture was basified    with a saturated aqueous sodium hydrogen carbonate solution, and    subsequently, the reaction mixture was made acidic with a saturated    aqueous citric acid solution. The mixture was extracted with    chloroform, and dried over magnesium sulfate. The solvent was    evaporated under reduced pressure. The residue was crystallized from    chloroform-hexane to give    5-bromo-2-chloro-1-(6-hydroxybenzo[b]thiophen-2-ylmethyl)-benzene    (2.01 g) as pale green crystals. ESI-Mass m/Z 351/353 (M−H).-   (2) The above    5-bromo-2-chloro-1-(6-hydroxy-benzo[b]thiophen-2-ylmethyl)benzene    (500 mg) was dissolved in N,N-dimethylformamide (5 ml), and thereto    were added iodoethane (0.23 ml) and potassium carbonate (390 mg).    The mixture was stirred at room temperature for 2 days. Added there    to was water, and the mixture was extracted with ethyl acetate. The    extract was washed with water and brine, and dried over magnesium    sulfate. The solvent was evaporated under reduced pressure, and the    residue was purified by silica gel column chromatography    (hexane:ethyl acetate=98:2-80:20) to give the desired    5-bromo-2-chloro-1-(6-ethoxybenzo[b]thiophen-2-ylmethyl)benzene (492    mg) as pale pink oil. APCI-Mass m/Z 381/383 (M+H).

REFERENCE EXAMPLE 1335-Bromo-2-chloro-3-(5-phenyl-2-thienylmethyl)thiophene

5-Bromo-2-chloro-3-thiophenecarboxylic acid (see Japanese UnexaminedPatent Publication No. 10-324632) and 2-phenylthiophene were treated ina manner similar to Reference Example 5 to give the target compound as acolorless solid. APCI-Mass m/Z 367/369 (M+H).

REFERENCE EXAMPLE 134 6-Fluoro-2-pyridylboronic acid pinacol ester

A solution of 2-bromo-6-fluoropyridine (1.0 g) in tetrahydrofuran (10ml) was cooled to −78° C. under argon atmosphere, and thereto was addeda solution of n-butyl lithium (2.59 M hexane solution, 2.24 ml) intetrahydrofuran (10 ml). The mixture was stirred at the same temperaturefor 45 minutes, and thereto was added dropwise a solution oftriisopropoxyborane (1.28 g) in tetrahydrofuran (10 ml). The mixture wasstirred at the same temperature for 2 hours, warmed, and further stirredat room temperature for one hour. Subsequently, a solution of pinacol(0.91 g) in tetrahydrofuran (10 ml) was added dropwise thereto, andstirred at room temperature for 20 minutes. Insoluble materials werefiltered off. The filtrate was extracted with 2.5% sodium hydroxide, andthe extract was cooled to 0° C., and was made weakly acidic with 2Naqueous hydrochloric acid solution. It was extracted with diethyl ether,washed with a small amount of brine, and dried over magnesium sulfate.The solvent was evaporated under reduced pressure and the residue wassolidified with hexane to give 6-fluoro-2-pyridylboronic acid pinacolester (850 mg) as a colorless solid. APCI-Mass m/Z 224 (M+H).

REFERENCE EXAMPLE 1355-Bromo-2-chloro-1-(6-phenyl-3-pyridylmethyl)benzene

-   (1) 5-Bromo-2-chlorobenzoic acid was treated in a manner similar to    Reference Example 4-(2) to give    N-methoxy-N-methyl-5-bromo-2-chlorobenzamide as a colorless solid.    APCI-Mass m/Z 278/280 (M+H).-   (2) The above N-methoxy-N-methyl-5-bromo-2-chlorobenzamide and    2,5-dibromopyridine were treated in a manner similar to Reference    Example 31-(4) to give 5-bromo-2-chlorophenyl 6-bromo-3-pyridyl    ketone as a pale yellow solid. APCI-Mass m/Z 374/376 (M+H).-   (3) The above 5-bromo-2-chlorophenyl 6-bromo-3-pyridyl ketone and    phenylboronic acid were treated in a manner similar to Reference    Example 20-(1) to give 5-bromo-2-chlorophenyl 6-phenyl-3-pyridyl    ketone as yellow crystals. APCI-Mass m/Z 372/374 (M+H).-   (4) The above 5-bromo-2-chlorophenyl 6-phenyl-3-pyridyl ketone was    treated in a manner similar to Reference Example 14-(1) to give the    desired 5-bromo-2-chloro-1-(6-phenyl-3-pyridylmethyl)benzene as    colorless crystals. APCI-Mass m/Z 358/360 (M+H).

REFERENCE EXAMPLE 1365-Bromo-2-chloro-1-(6-isopropyloxybenzo[b]thiophen-2-ylmethyl)benzene

5-Bromo-2-chloro-1-(6-hydroxybenzo[b]thiophen-2-ylmethyl)-benzeneobtained in Reference Example 132-(1) and 2-iodopropane were treated ina manner similar to Reference Example 132-(2) to give the titledcompound. APCI-Mass m/Z 395/397 (M+H).

REFERENCE EXAMPLE 1374-Bromo-1-fluoro-2-(5-(2-pyridyl)-2-thienylmethyl)naphthalene

-   (1) A solution of 2,2,6,6-tetramethylpiperidine (4.13 ml) in    tetrahydrofuran (40 ml) was cooled to −78° C. under argon    atmosphere, and added dropwise thereto was n-butyl lithium (2.44 M    hexane solution, 10.0 ml). The mixture was stirred at the same    temperature for 30 minutes, and added dropwise thereto at −78° C.    was a solution of 1-bromo-4-fluoronaphthalene (5.0 g) in    tetrahydrofuran (20 ml). The mixture was stirred at the same    temperature for 1 hour, and added dropwise thereto at −78° C. was    N,N-dimethylformamide (5.16 ml). The mixture was stirred at the same    temperature for 1 hour, and added thereto was a saturated aqueous    ammonium chloride solution, and the mixture was extracted with ethyl    acetate. The extract was washed with water and dried over magnesium    sulfate, and the solvent was evaporated under reduced pressure. The    residue was crystallized from diisopropyl ether and hexane to give    4-bromo-1-fluoro-2-naphthaldehyde (4.43 g) as pale yellow crystals.    APCI-Mass m/Z 267/269 (M+NH₄).-   (2) The above 4-bromo-1-fluoro-2-naphthaldehyde and    2-(2-pyridyl)thiophene were treated in a manner similar to Reference    Example 120 to give the desired    4-bromo-1-fluoro-2-(5-(2-pyridyl)-2-thienylmethyl)naphthalene as    colorless powder. APCI-Mass m/Z 398/400 (M+H).

REFERENCE EXAMPLE 1385-Bromo-2-chloro-1-(6-ethyl-3-pyridylmethyl)benzene

-   (1) 5-Bromo-2-chlorophenyl 6-bromo-3-pyridyl ketone (3.2 g) from    Reference Example 135-(2) was dissolved in tetrahydrofuran (80 ml),    and added thereto were triethylaluminium (1.0 M hexane solution, 9.9    ml), tetrakis(triphenylphosphine)palladium(0) (570 mg) and    cerium(III) chloride (7.3 g), and the mixture was stirred at 30° C.    for 1.5 hours. The reaction mixture was diluted with methanol, and    the reaction solution was basified with a saturated aqueous sodium    hydrogen carbonate solution. The insoluble materials were filtered    off and, the filtrate was extracted with ethyl acetate and dried    over magnesium sulfate. The solvent was evaporated under reduced    pressure, and the residue was purified by silica gel column    chromatography (hexane:ethyl acetate=99:1-85:15) to give    5-bromo-2-chlorophenyl 6-ethyl-3-pyridyl ketone (1.98 g) as a    colorless solid. APCI-Mass m/Z 324/326 (M+H).-   (2) The above 5-bromo-2-chlorophenyl 6-ethyl-3-pyridyl ketone was    treated in a manner similar to Reference Example 14-(1) to give the    desired 5-bromo-2-chloro-1-(6-ethyl-3-pyridylmethyl)benzene as a    colorless oil. APCI-Mass m/Z 310/312 (M+H).

REFERENCE EXAMPLE 139 6-Ethylbenzo[b]thiophene

-   (1) 4-Bromo-2-flurobenzaldehyde and ethyl thioglycolate were treated    in a manner similar to Reference Example 31-(1) to give    6-bromo-2-ethoxycarbonylbenzo[b]thiophene as a colorless solid.-   (2) The above 6-bromo-2-ethoxycarbonylbenzo[b]thiophene was treated    in a manner similar to Reference Example 138-(1) to give    6-ethyl-2-ethoxycarbonylbenzo[b]thiophene as colorless oil.    APCI-Mass m/Z 235 (M+H).-   (3) The above 6-ethyl-2-ethoxycarbonylbenzo[b]thiophene (1.26 g) was    dissolved in tetrahydrofuran (4 ml) and methanol (8 ml), and added    thereto was lithium hydroxide monohydrate (677 mg), and the mixture    was stirred at room temperature overnight. The solvent was    evaporated under reduced pressure, and the residue was dissolved in    water and the solution was made acidic with a 10% aqueous    hydrochloric acid solution. The precipitates were collected by    filtration and washed with water to give    6-ethylbenzo[b]thiophen-2-ylcarboxylic acid (1.15 g) as colorless    crystals. ESI-1-Mass m/Z 205 (M−H).-   (4) The above 6-ethylbenzo[b]thiophen-2-ylcarboxylic acid was tread    in a manner similar to Reference Example 47-(2) to give the desired    6-ethylbenzo[b]thiophene as colorless oil.

REFERENCE EXAMPLE 1405-Bromo-2-chloro-1-(1-oxo-2-isoindolinylmethyl)benzene

-   (1) 5-Bromo-2-chlorobenzyl alcohol (3.0 g) was dissolved in toluene    (30 ml), and added thereto were thionyl chloride (2.35 ml) and    pyridine (two drops), and the mixture was heated under stirring at    100° C. for 2 hours. The mixture was cooled, washed with a saturated    aqueous sodium hydrogen carbonate solution and brine, and dried over    sodium sulfate. The solvent was evaporated under reduced pressure to    give 5-bromo-2-chlorobenzyl chloride (3.34 g) as pale brown oil,    which was used in the subsequent step without further purification.-   (2) The above 5-bromo-2-chlorobenzyl chloride (3.34 g) was dissolved    in N,N-dimethylformamide (30 ml), and added thereto was potassium    phthalimide (2.63 g), and the mixture was heated under stirring at    70° C. for 3 hours. The reaction solution was poured into water, and    the mixture was extracted with ethyl acetate. The extract was washed    with brine, and dried over sodium sulfate. The solvent was    evaporated under reduced pressure, and the residue was crystallized    from diisopropyl ether to give    5-bromo-2-chloro-1-(phthalimid-2-ylmethyl)-benzene (3.33 g) as    colorless crystals. APCI-Mass m/Z 350/352 (M+H).-   (3) The above 5-bromo-2-chloro-1-(phthalimid-2-ylmethyl)-benzene    (4.3 g) was dissolved in acetic acid (43 ml), and added thereto was    zinc powder (8.02 g), and the mixture was heated at reflux for 3    days. The mixture was cooled and diluted with chloroform and it was    basified with an aqueous sodium hydroxide solution. The organic    layer was dried over sodium sulfate, and the solvent was evaporated    under reduced pressure. The residue was purified by silica gel    column chromatography (hexane:ethyl acetate=6:1-4:1) to give the    desired 5-bromo-2-chloro-1-(1-oxo-2-isoindolinylmethyl)benzene    (1.39 g) as colorless powder. APCI-Mass m/Z 336/338 (M+H).

REFERENCE EXAMPLE 1415-Bromo-2-chloro-1-(1-phenyl-4-pyrazolylmethyl)benzene

-   (1) A solution of 1-phenyl-4-bromopyrazole (see M. A. Khan, et al.,    Can. J. Chem., (1963) 41 1540) (2.23 g) in diethyl ether (30 ml) wad    cooled to −78° C. under argon atmosphere, and added dropwise thereto    was n-butyl lithium (1.59 M hexane solution, 6.9 ml). The mixture    was stirred at −20° C. to −10° C. for 5 hours, and added dropwise    thereto at the same temperature was a solution of    5-bromo-2-chlorobenzaldehyde (2.19 g) obtained in Reference Example    16-(1) in diethyl ether (30 ml). The mixture was stirred at the same    temperature for 30 minutes, and added thereto was tetrahydrofuran    (30 ml), and the mixture was stirred at 0° C. for further 30    minutes. A saturated aqueous ammonium chloride solution was added    thereto, and the mixture was extracted with ethylacetate. The    extract was washed with brine and dried over sodium sulfate. The    solvent was evaporated under reduced pressure, and the residue was    purified by silica gel column chromatography (hexane:ethyl    acetate=83:17-80:20) to give    5-bromo-2-chlorophenyl-1-phenyl-4-pyrazolylmethanol (831 mg) as    yellow oil. APCI-Mass m/Z 363/365 (M+H).-   (2) The above 5-bromo-2-chlorophenyl-1-phenyl-4-pyrazolylmethanol    was treated in a manner similar to Reference Example 120-(2) to give    the desired 5-bromo-2-chloro-1-(1-phenyl-4-pyrazolylmethyl)benzene    as colorless powder. APCI-Mass m/Z 347/349 (M+H).

REFERENCE EXAMPLE 1425-Bromo-2-chloro-1-(6-n-propyloxybenzo[b]thiophen-2-yl-methyl)benzene

5-Bromo-2-chloro-1-(6-hydroxybenzo[b]thiophen-2-ylmethyl)benzeneobtained in Reference Example 132-(1) and 1-bromopropane were treated ina manner similar to Reference Example 132-(2) to give the targetcompound. APCI-Mass m/Z 395/397 (M+H).

REFERENCE EXAMPLE 1435-Bromo-2-chloro-1-(6-(2-fluoroethyloxy)benzo[b]thiophen-2-ylmethyl)benzene

5-Bromo-2-chloro-1-(6-hydroxybenzo[b]thiophen-2-ylmethyl)-benzeneobtained in Reference Example 132-(1) and 1-bromo-2-fluoroethane weretreated in a manner similar to Reference Example 132-(2) to give thetarget compound. APCI-Mass m/Z 399/401 (M+H).

REFERENCE EXAMPLE 144 5-Tri-n-butylstannanylthiazole

The target compound was prepared according to a method described in WO03/087104.

REFERENCE EXAMPLE 145 4-Tri-n-butylstannanylthiazole

The target compound was prepared according to a method described in WO03/087104.

REFERENCE EXAMPLE 146 Tri-n-butyl(6-methoxy-2-pyridyl)tin

The target compound was prepared according to a method described in P.Gros, et al., Synthesis (1999) 754.

REFERENCE EXAMPLE 1475-Bromo-2-chloro-1-(5-ethoxybenzo[b]thiophen-2-ylmethyl)-benzene

-   (1)    5-Bromo-2-chloro-1-(5-methoxybenzo[b]thiophene-2-yl-methyl)benzene    obtained in Reference Example 54 was treated in a manner similar to    Reference Example 132-(1) to give    5-bromo-2-chloro-1-(5-hydroxybenzo[b]thiophen-2-ylmethyl)-benzene.    ESI-Mass m/Z 351/353 (M−H).-   (2) The above    5-bromo-2-chloro-1-(5-hydroxy-benzo[b]thiophen-2-ylmethyl)benzene    and iodoethane were treated in a manner similar to Reference Example    132-(2) to give the desired    5-Bromo-2-chloro-1-(5-ethoxybenzo[b]thiophene-2-ylmethyl)-benzene.    APCI-Mass m/Z 382/380 (M+H).

REFERENCE EXAMPLE 1485-Bromo-2-chloro-1-(5-(1-pyrazolyl)-2-thienylmethyl)benzene

1-(2-thienyl)pyrazole (see: Chemica Scripta (1979) 13, 157-161) and5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1) wereused and treated in a manner similar to Reference Example 7 to give thetitle compound as colorless solid. APCI-Mass m/z 353/355 (M+H).

REFERENCE EXAMPLE 1495-Bromo-2-chloro-1-(tert-butyldiphenylsilyloxymethyl)-benzene

To a solution of 5-Bromo-2-chlorobenzylalcohol (5.15 g) inN,N-dimethylformamide (50 ml) was added diisopropylethylamine (19.8 ml)and tert-butyldiphenylchlorosilane (11.9 ml), and the mixture wasstirred at room temperature for 2 days. Under ice-cooling, to themixture was added water, and the mixture was extracted with ethylacetate. The extract was washed with successively with 0.4 M aqueoushydrochloric acid solution (twice), water, a saturated aqueous sodiumhydrogen carbonate solution and brine, and dried over magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue waspurified by an aminosilane-treated silica gel column chromatography(hexane) to give5-bromo-2-chloro-1-(tert-butyldiphenylsiloxymethyl)benzene 77 (10.79 g)as colorless oil. APCI-Mass m/Z 476/478 (M+NH₄).

REFERENCE EXAMPLE 150 2-Fluoropyridin-4-boronic acid

The target compound was prepared according to a method described inTetrahedron (2002) 58, 4369-4373.

REFERENCE EXAMPLE 151 3-Difluoromethoxybenzeneboronic acid

A solution of 3-(difluoromethoxy)benzene (3.0 g) and triisopropoxyborane(2.78 g) in tetrahydrofuran (15 ml) was cooled to −78° C. under argonatmosphere, and thereto was added a solution of n-butyl lithium (1.59 Mhexane solution, 9.3 ml). The mixture was stirred at same temperaturefor 10 minutes, warmed, and further stirred at room temperatureovernight. Thereto was added 3N aqueous hydrochloric acid solution (10ml), and the mixture was stirred at room temperature for 5 minutes. Themixture was extracted with ethyl acetate. The extract was washed withbrine, and dried over sodium sulfate. The solvent was evaporated underreduced pressure. The residue was crystallized from hexane to give3-difluoromethoxybenzene-boronic acid (1.6 g) as colorless crystals.

REFERENCE EXAMPLE 152 Tri-n-butyl(2-cyano-5-pyridyl)tin

5-Bromo-2-cyanopyridine was treated in a manner similar to the methodsdescribed in European Patent Publication No. 93-00867.

REFERENCE EXAMPLE 1535-Bromo-2-chloro-1-(6-difluoromethoxybenzo[b]thiophen-2-yl-methyl)benzene

5-Bromo-2-chloro-1-(6-hydroxybenzo[b]thiophen-2-ylmethyl)-benzene (1.8g) obtained in Reference Example 132-(1) was dissolved indimethylformamide (15 ml), and added thereto were methyl2-chloro-2,2-difluoroacetate (1.63 ml) and potassium carbonate (2.28 g),and the mixture was stirred at 100° C. for 1.5 hours under argonatmosphere. The reaction mixture was acidified with 2N aqueous HClsolution and extracted with ethyl acetate. The organic layer was washedwith brine and dried over magnesium sulfate. The solvent was evaporatedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography (hexane) to give5-bromo-2-chloro-1-(6-difluoromethoxybenzo[b]thiophen-2-yl-methyl)benzene(695 mg) as a colorless solid. GC-Mass m/Z 402/404 (M+).

REFERENCE EXAMPLE 1545-Bromo-1-(6-difluoromethoxybenzo[b]thiophen-2-ylmethyl)-2-methylbenzene

-   (1) 6-Methoxybenzo[b]thiophene (see WO 97/25033) and    5-bromo-2-methylbenzaldehyde obtained in Reference Example 4 were    treated in a manner similar to Reference Example 7 to give 5-Bromo    -1-(6-methoxybenzo[b]thiophen-2-ylmethyl)-2-methyl-benzene.    APCI-Mass m/Z 347/349 (M+NH₄).-   (2) The above    5-bromo-1-(6-methoxybenzo[b]thiophen-2-ylmethyl)-2-methyl-benzene    was treated in a manner similar to Reference Example 132-(1) to give    5-Bromo-1-(6-hydroxybenzo[b]thiophen-2-yl-methyl)-2-methylbenzene.    ESI-Mass m/Z 331/333 (M−H).-   (3) The above    5-bromo-1-(6-hydroxybenzo[b]thiophen-2-yl-methyl)-2-methylbenzene    was treated in a manner similar to Reference Example 153 to give the    desired    5-bromo-1-(6-difluoromethoxybenzo[b]thiophen-2-ylmethyl)-2-methylbenzene    as colorless oil. GC-Mass m/Z 382/384 (M+).

REFERENCE EXAMPLE 155 (6-Cyanopyridin-2-yl)trimethyltin

2-Bromo-6-cyanopyridine (see Japanese Patent Publication 04-253974) (1.5g) and hexamethylditin (2.69 g) were dissolved in dimethoxyethane (50ml) and thereto was added tetrakis(triphenylphosphine)palladium(0) (972mg). The mixture was refluxed for 5 hours. The solvent was evaporatedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography (hexane:ethyl acetate=100:1) to give(6-cyanopyridin-2-yl)trimethyltin (980 mg) as colorless oil. APCI-Massm/Z 265/267/269 (M+H).

REFERENCE EXAMPLE 1565-Bromo-2-methyl-1-(5-(1-pyrazolyl)-2-thienylmethyl)benzene

1-(2-thienyl)pyrazole (see Chemica Scripta (1979) 13, 157-161) and5-bromo-2-methybenzaldehyde obtained in Reference Example 4 were usedand treated in a manner similar to Reference Example 7 to give the titlecompound as colorless oil. APCI-Mass m/z 333/335 (M+H).

REFERENCE EXAMPLE 1575-Bromo-1-(6-ethoxybenzo[b]thiophen-2-ylmethyl)-2-methyl-benzene

5-Bromo-1-(6-hydroxybenzo[b]thiophen-2-ylmethyl)-2-methyl-benzeneobtained in Reference Example 154-(2) and iodoethane were treated in amanner similar to Reference Example 132-(2) to give the desired5-bromo-1-(6-ethoxy-benzo[b]thiophene-2-ylmethyl)-2-methylbenzene aspale yellow wax. APCI-Mass m/Z 361/363 (M+H).

REFERENCE EXAMPLE 1585-Bromo-1-(5-methoxybenzo[b]thiophen-2-ylmethyl)-2-methyl-benzene

5-Methoxybenzo[b]thiophene (see WO 97/25033) and5-bromo-2-methylbenzaldehyde obtained in Reference Example 4 weretreated in a manner similar to Reference Example 7 to give5-bromo-1-(5-methoxybenzo[b]thiophen-2-ylmethyl)-2-methyl-benzene ascolorless wax.

REFERENCE EXAMPLE 1595-Bromo-1-(5-(2-fluoroethyloxy)benzo[b]thiophen-2-ylmethyl)-2-methylbenzene

-   (1)    5-Bromo-1-(5-methoxybenzo[b]thiophene-2-yl-methyl)-2-methylbenzene    obtained in Reference Example 158 was treated in a manner similar to    Reference Example 132-(1) to give    5-bromo-1-(5-hydroxybenzo[b]thiophen-2-ylmethyl)-2-methyl-benzene as    colorless powder. ESI-Mass m/Z 331/333 (M−H).-   (2) The above    5-bromo-1-(5-hydroxybenzo[b]thiophen-2-yl-methyl)-2-methylbenzene    and 1-bromo-2-fluoroethane were treated in a manner similar to    Reference Example 132-(2) to give the desired    5-bromo-1-(5-(2-fluoroethyloxy)-benzo[b]thiophene-2-ylmethyl)-2-methylbenzene.

REFERENCE EXAMPLE 1605-Bromo-1-(5-ethoxybenzo[b]thiophen-2-ylmethyl)-2-methyl-benzene

5-Bromo-1-(5-hydroxybenzo[b]thiophen-2-ylmethyl)-2-methyl-benzeneobtained in Reference Example 159-(1) and iodoethane were treated in amanner similar to Reference Example 132-(2) to give the desired5-bromo-1-(5-ethoxybenzo[b]thiophene-2-ylmethyl)-2-methylbenzene ascolorless powder.

REFERENCE EXAMPLE 1615-Bromo-2-chloro-1-(5-(2-fluoroethyloxy)benzo[b]thiophene-2ylmethyl)benzene

5-Bromo-2-chloro-1-(5-hydroxybenzo[b]thiophen-2-ylmethyl)-benzeneobtained in Reference Example 147-(1) and 1-bromo-2-fluoroethane weretreated in a manner similar to Example 132-(2) to give the targetcompound.

REFERENCE EXAMPLE 1625-Bromo-1-(6-(2-fluoroethyloxy)benzo[b]thiophen-2-ylmethyl)2-methylbenzene

5-Bromo-1-(6-hydroxybenzo[b]thiophen-2-ylmethyl)-2-methyl-benzeneobtained in Reference Example 154-(2) and 1-bromo-2-fluoroethane weretreated in a manner similar to Example 132-(2) to give the targetcompound as colorless wax. APCI-Mass m/Z 379/381 (M+H).

REFERENCE EXAMPLE 163 4-(Difluoromethoxy)phenylboronic acid

A solution of (4-bromophenoxy)difluoromethane (3 g) and triisopropylborate (3.42 ml) in tetrahydrofuran (15 ml) was cooled to −78° C. underargon atmosphere, and thereto was added a solution of n-butyl lithium(1.59M hexane solution, 3.42 ml). The mixture was stirred at roomtemperature overnight. Added thereto was 6N aqueous hydrochloric acid at0° C., and the mixture was extracted with ethyl acetate. The extract waswashed with brine, and dried over magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was triturated withcold hexane to give 4-(difluoromethoxy)phenylboronic acid (1.88 g) ascolorless solid.

REFERENCE EXAMPLE 164 Tri-n-butyl(3-methyl-5-isooxazolyl)tin

The target compound was prepared according to a method described inBioorg. & Med. Chem. Lett. (2003) 13, 4117-4120.

REFERENCE EXAMPLE 1655-Bromo-2-chloro-1-(2-trifluoromethyl-5-pyridylmethyl)-benzene

-   (1) A solution of 5-Bromo-2-trifluoromethylpyridine (5.3 g) (see    Eur. J. Org. Chem. (2003) 1159-1168) in tetrahydrofuran (70 ml) was    cooled to 0° C. under argon atmosphere, and thereto was added    dropwise isopropylmagnesium chloride (1 mol/l tetrahydrofuran    solution, 23.45 ml). The reaction mixture was stirred at the same    temperature for 2 hours, and thereto was added dropwise a solution    of 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1)    (5.15 g) in tetrahydrofuran (20 ml). The mixture was stirred at the    same temperature for 60 minutes, and thereto was added a saturated    ammonium chloride solution, and the reaction mixture was warmed to    room temperature. The mixture was extracted with ethyl acetate, and    the extract was dried over magnesium sulfate, and the solvent was    evaporated under reduced pressure. The residue was purified by    silica gel column chromatography (hexane:ethyl acetate=98:2-85:15)    to give    (5-Bromo-2-chloro)phenyl-(2-trifluoromethyl-5-pyridyl)methanol    (4.56 g) as a pale brown syrup. APCI-Mass m/Z 366/368 (M+H).-   (2) The above    (5-Bromo-2-chloro)phenyl-(2-trifluoromethyl-5-pyridyl)methanol    (4.55 g) was dissolved in dichloromethane (50 ml) and toluene (50    ml), and added thereto was manganese (IV) oxide (5.39 g), and the    mixture was stirred at room temperature overnight. Insoluble    materials were filtered off, and the solvent was evaporated under    reduced pressure. The resultant residue was purified by silica gel    column chromatography (hexane:ethyl acetate=98:2-92:8) to give    (5-Bromo-2-chloro)phenyl(2-trifluoromethyl-5-pyridyl) ketone    (2.64 g) as a pale yellow syrup. APCI-Mass m/Z 364/366 (M+H).-   (3) The above (5-Bromo-2-chloro)phenyl (2-trifluoromethyl-5-pyridyl)    ketone was treated in a manner similar to Reference Example 14-(1)    to give the desired    5-Bromo-2-chloro-1-(2-trifluoromethyl-5-pyridylmethyl)-benzene.    APCI-Mass m/Z 350/352 (M+H).

REFERENCE EXAMPLE 166 4-Methyl-2-tributylstannanylthiazole

A solution of n-butyl lithium (2.71 M hexane solution, 3.9 ml) intetrahydrofuran (10 ml) was cooled to −78° C. under argon atmosphere,and thereto was added dropwise a solution of 4-methylthiazole (1.0 g) intetrahydrofuran (10 ml). The mixture was stirred at same temperature forone hour and thereto was added dropwise a solution of tri-n-butyltinchloride (3.6 g) in tetrahydrofuran (10 ml). The mixture was stirred atsame temperature for 30 minutes, warmed, and further stirred at roomtemperature overnight. Thereto was added water, and the mixture wasextracted with diethyl ether. The extract was washed with brine, anddried over sodium sulfate. The solvent was evaporated under reducedpressure. The residue was purified by alumina column chromatography(hexane) to give the title compound (1.76 g) as oil. APCI-Mass m/z386/388 (M+H).

REFERENCE EXAMPLE 167 2-Fluoropyridine-3-boronic acid

The target compound was prepared according to a method described inTetrahedron (2002) 58, 3323-3328.

REFERENCE EXAMPLE 1684-Bromo-2-(5-chloro-2-thienylmethyl)-1-methoxynaphthalene

2,4-Dibromo-1-methoxynaphthalene (see Org. Lett. (2003) 5, 831) and5-chloro-2-thiophenecarboxaldehyde were treated in a manner similar toReference Example 1 to give4-Bromo-2-(5-chloro-2-thienylmethyl)-1-methoxynaphthalene.

REFERENCE EXAMPLE 1692-(2-(6-Chloro)pyridine)-4,4,5,5-tetramethyl-1,3-dioxa-borolane

The target compound was prepared according to a method described inTetrahedron (2003) 59, 10043-10049.

REFERENCE EXAMPLE 170 2-Methyl-4-tri-n-butylstannanylthiazole

The target compound was prepared according to a method described inTetrahedron (2003), 9979-9984.

REFERENCE EXAMPLE 1712-(4-(2-Methyl)pyridine)-4,4,5,5-tetramethyl-1,3-dioxaborolane

The target compound was prepared according to a method described inUnited States Patent Publication No. 2003-024914.

REFERENCE EXAMPLE 172 1-(β-D-glucopyranosyl)-5-chloroindole

5-Chloro-2,3-dihydro-(1H)-indole was treated in a manner similar to themethods described in Eur. J. Med. Chem. (2004) 39, 453-458 to give thetitle compound. APCI-Mass m/z 314/316 (M+H).

REFERENCE EXAMPLE 1735-Bromo-2-chloro-1-(5-(5-fluorothiazol-2-yl)-2-thienylmethyl)benzene

-   (1) 2-Bromothiazole (15.0 g) and 2-thiopheneboronic acid (14.0 g)    were dissolved in dimethoxyethane (150 ml). To the mixture was added    bis(triphenyl)phosphine palladium(II) dichloride (3.2 g) and 2M    sodium carbonate (137 ml), and the mixture was refluxed under argon    atmosphere for 2 hours. The mixture was cooled to room temperature,    and the reaction solution was diluted with ethyl acetate, and washed    with water. The organic layer was collected, dried over sodium    sulfate, and the solvent was evaporated under reduced pressure. The    residue was purified by silica gel column chromatography    (hexane:ethyl acetate=96:4) to give 2-(2-thienyl)thiazole (9.87 g)    as oil. APCI-Mass m/z 168 (M+H).-   (2) The above compound (3.17 g) was treated in a manner similar to    Reference Example 121 to give 5-fluoro-2-(2-thienyl)-thiazole    (1.58 g) as oil. APCI-Mass m/z 186 (M+H).-   (3) The above compound (1.58 g) was dissolved in chloroform (16 ml),    cooled to 0° C., and thereto was added dropwise a solution of    bromine (1.43 g) in chloroform (15 ml). The mixture was stirred at    the same temperature for one hour, warmed, and further stirred at    room temperature for one hour. The reaction mixture was poured into    saturated aqueous sodium hydrogen carbonate solution, and the    mixture was extracted with chloroform. The extract was washed with    10% aqueous sodium thiosulfate solution, brine, and dried over    sodium sulfate. The solvent was evaporated under reduced pressure.    The residue was purified by silica gel column chromatography    (hexane:ethyl acetate=97:3) to give    2-(5-bromo-2-thienyl)-5-fluoro-thiazole (1.81 g) as a pale yellow    solid.-   (4) The above compound (300 mg) and 5-bromo-2-chloro-benzaldehyde    obtained in Reference Example 16-(1) were used and treated in a    manner similar to Reference Example 7 to give the desired    5-bromo-2-chloro-1-(5-(5-fluorothiazol-2-yl)-2-thienylmethyl)benzene    (199 mg) as a pale yellow powder.

REFERENCE EXAMPLE 174 1-(β-D-glucopyranosyl)-4-chloroindole

-   (1) 4-Chloroindole (3.15 g) was dissolved in trifluoroacetic acid    (32 ml), thereto was added triethylsilane (8.3 ml) and the mixture    was heated at 50° C. with stirring for 30 minutes. The resultant    mixture was cooled to room temperature, and trifluoroacetic acid was    evaporated under reduced pressure. To the residue was added a    saturated aqueous sodium hydrogen carbonate solution, and the    mixture was extracted with ethyl acetate twice. The organic layer    was dried over magnesium sulfate, and the solvent was evaporated    under reduced pressure. The residue was purified by silica gel    column chromatography (hexane:ethyl acetate=100:0-80:20) to give    4-chloro-2,3-dihydro-(1H)-indole (2.89 g) as colorless oil.    APCI-Mass m/z 154/156 (M+H).-   (2) The above 4-chloro-2,3-dihydro-(1H)-indole was treated in a    manner similar to described in Eur. J. Med. Chem. (2004) 39, 453-458    to give the title compound. APCI-Mass m/z 314/316 (M+H).

REFERENCE EXAMPLE 175 1-(β-D-glucopyranosyl)-6-chloroindole

6-Chloroindole was treated in a manner similar to Reference Example 174to give the title compound. APCI-Mass m/z 314/316 (M+H).

Pharmacological Experiment

1. Assay for SGLT2 Inhibition

Test Compounds:

Compounds described in the above examples were used for the SGLT2inhibition assay.

Method:

CHOK1 cells expressing human SGLT2 were seeded in 24-well plates at adensity of 400,000 cells/well in F-12 nutrient mixture (Ham's F-12)containing 10% fetal bovine serum, 400 μg/ml Geneticin, 50 units/mlsodium penicillin G (Gibco-BRL) and 50 μg/ml streptomycin sulfate. After2 days of culture at 37° C. in a humidified atmosphere containing 5%CO₂, cells were washed once with the assay buffer (137 mM NaCl, 5 mMKCl, 1 mM CaCl₂, 1 mM MgCl₂, 50 mM Hepes, and 20 mM Tris, pH 7.4) andincubated with 250 μl of the buffer containing test compounds for 10 minat 37° C. Test compounds were dissolved in DMSO. The final concentrationof DMSO was 0.5%. The transport reaction was initiated by addition of 50μl [¹⁴C]-methyl-α-D-glucopyranoside (¹⁴C-AMG) solution (finalconcentration, 0.5 mM). After incubation for 2 hours at 37° C., theuptake was stopped by aspiration of the incubation mixture, the cellswere washed three times with ice-cold PBS. Then, cells were solubilizedwith 0.3 N NaOH and aliquots were taken for determination ofradioactivity by a liquid scintillation counter. Nonspecific AMG uptakewas defined as that which occurred in the presence of 100 μM ofphlorizin, a specific inhibitor of sodium-dependent glucosecotransporter. Specific uptake was normalized for the proteinconcentrations measured by the method of Bradford. The 50% inhibitoryconcentration (IC₅₀) values were calculated from dose-response curves byleast square method.

Results:

Results are shown in the following table:

Test Compounds (Example No.) IC50 (nM) 69 7.9 70 7.0 71 6.6 72 4.6 781.7 79 9.0 80 6.8 83 1.3 84 2.2 86 2.8 87 3.4 88 2.6 89 3.0 90 2.0 1203.4 122 8.2 123 1.4 127 1.3 130 2.4 140 5.9 142 5.6 144 4.1 145 4.0 1462.2 148 2.8 151 2.5 155 1.7 156 1.1 168 2.3 169 3.6 170 3.5 173 8.0 1767.7 177 6.7 178 5.1 179 9.8 183 9.5 185 5.6 186 5.4 187 4.3 188 1.6 1892.4 190 3.1 191 7.7 192 7.4 193 0.9 194 2.6 197 2.0 201 8.2 202 8.7 2041.4 207 0.6 208 2.4 209 3.9 210 1.0 211 1.2 212 2.6 213 5.6 214 1.5 2154.3 216 3.3 217 3.6 218 2.4 219 6.7 221 5.5 222 1.8 223 3.1 224 5.9 2251.5 226 1.2 227 3.2 228 3.6 229 2.7 230 4.0 231 3.5 232 4.0 233 2.9 2342.4 235 2.6 236 4.4 237 2.8 238 1.6 240 1.2 241 1.0 242 4.6 244 1.2 2466.4 247 2.5 248 5.1 249 4.3 250 4.2 251 3.6 252 1.4 253 1.6 254 1.7 2556.5 256 3.1 257 3.3 260 2.3 264 1.5 265 3.4 266 3.2 267 1.5 268 2.52. Urinary Glucose Excretion Test in RatsTest Compounds:

Compounds described in the above examples were used for the urinaryglucose excretion test in rats.

Methods:

6-week-old male Spraue-Dawley (SD) rats were housed in individualmetabolic cages with free access to food and water from 2 days prior tothe experiment. On the morning of the experiment, rats were administeredvehicle (0.2% carboxymethyl cellulose solution containing 0.2% Tween80)or test compounds (30 mg/kg) by oral gavage at a volume of 10 ml/kg.Then, urine of the rat was collected for 24 hours, and the urine volumewas measured. Subsequently, the glucose concentration in urine wasquantified using the enzymatic assay kit and the daily amount of glucoseexcreted in urine per individual was calculated.

Results:

Urinary glucose amount ranges are depicted by A and B. These ranges areas follows: A≧2000 mg; 2000 mg>B≧1000 mg.

Test compounds (Example No.) Urinary glucose 22 A 25 B 69 B 70 A 81 B 83A 84 A 88 B 89 B 120 A 123 A 127 A 133 B 140 B 142 A 144 B 146 A 148 B151 B 155 A 156 A 168 A 169 B 170 B 177 A 178 B 189 B 194 A 195 B 204 A207 A 208 A 209 B 210 B 214 B 216 A 217 B 221 B 223 A 226 B 227 B 228 B229 B 230 A 231 B 232 B 233 B 235 A 236 B 237 B 238 A 247 A 248 B 251 A252 B

1. A compound of Formula (I):

wherein Ring A is

wherein R^(1a), R^(2a), R^(3a), R^(1b), R^(2b), and R^(3b) are eachindependently a hydrogen atom, a halogen atom, a hydroxy group, analkoxy group, an alkyl group, a haloalkyl group, a haloalkoxy group, ahydroxyalkyl group, an alkoxyalkyl group, an alkoxyalkoxy group, analkenyl group, an alkynyl group, a cycloalkyl group, acycloalkylidenemethyl group, a cycloalkenyl group, a cycloalkyloxygroup, a phenyl group, a phenylalkoxy group, a cyano group, a nitrogroup, an amino group, a mono- or di-alkylamino group, an alkanoylaminogroup, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, amono- or di-alkylcarbamoyl group, an alkanoyl group, analkylsulfonylamino group, a phenylsulfonylamino group, an alkylsulfinylgroup, an alkylsulfonyl group, or a phenylsulfonyl group, and Ring B is

wherein R^(4a) is a phenyl group substituted by a halogen atom, a cyanogroup, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxygroup, an alkylenedioxy group, an alkyleneoxy group, or a mono- ordi-alkylamino group; or a heterocyclyl group substituted by a halogenatom, a cyano group, an alkyl group, a haloalkyl group, an alkoxy group,or a haloalkoxy group, where the hererocyclyl group is a thienyl group,a pyridyl group, a pyrimidinyl group, a pyrazinyl group, a pyrazonylgroup, a thiazonyl group, a quinolyl group, or a tetrazolyl group;R^(5a) is a hydrogen atom; X is a carbon atom; and Y is -(CH₂)_(n)-(wherein n is 1 or 2); or a pharmaceutically acceptable salt thereof. 2.The compound, or a pharmaceutically acceptable salt thereof according toclaim 1, wherein R^(1a), R^(2a), R^(3a), R^(1b), R^(2b), and R^(3b) areeach independently a hydrogen atom, a halogen atom, a lower alkyl group,a halo-lower alkyl group, a lower alkoxy group, or a phenyl group;R^(4a) is a phenyl group substituted by halogen atom, a cyano group, alower alkyl group, a halo-lower alkyl group, a lower alkoxy group, ahalo-lower alkoxy group, a methylenedioxy group, an ethyleneoxy group,or a mono- or di-lower alkylamino group; or a heterocyclyl groupsubstituted by a halogen atom, a cyano group, a lower alkyl group, or alower alkoxy group.
 3. The compound, or a pharmaceutically acceptablesalt thereof according to claim 2, wherein Ring A is

wherein R^(1a) is a halogen atom, a lower alkyl group, or a lower alkoxygroup, and R^(2a) and R^(3a) are hydrogen atoms; R^(4a) is a phenylgroup substituted by a substituent selected from the group consisting ofa halogen atom, a cyano group, a lower alkyl group, a halo-lower alkylgroup, a lower alkoxy group, a halo-lower alkoxy group, and a mono- ordi-lower alkylamino group; or a heterocyclyl group substituted by ahalogen atom, a cyano group, a lower alkyl group, a lower alkoxy group,and Y is -CH₂.
 4. The compound, or a pharmaceutically acceptable saltthereof according to claim 3, wherein R^(4a) is a phenyl groupsubstituted by a halogen atom, a cyano group, a lower alkyl group, ahalo-lower alkyl group, a lower alkoxy group, or a halo-lower alkoxygroup; or a heterocyclyl group substituted by a halogen atom, a cyanogroup, a lower alkyl group, or a lower alkoxy group.
 5. A compoundrepresented by the following formula:

wherein R^(A) is a halogen atom, or a lower alkyl group; and Ring C is aphenyl group substituted by 1-3 substituents selected from the groupconsisting of a halogen atom, a cyano group, a lower alkyl group, ahalo-lower alkyl group, a lower alkoxy group, a halo-lower alkoxy group,a methylenedioxy group, an ethyleneoxy group, a mono- or di-loweralkylamino group; or a heterocyclyl group substituted by 1-3substituents selected from the group consisting of a halogen atom, acyano group, a lower alkyl group, a halo-lower alkyl group, a loweralkoxy group, a halo-lower alkoxy group; where the heterocyclyl group isa thienyl group, a pyridyl group, a pyrimidinyl group, a pyrazinylgroup, a pyrazolyl group, a thiazolyl group, a quinolyl group, ortetrazonyl group; or a pharmaceutically acceptable salt thereof.
 6. Thecompound, or a pharmaceutically acceptable salt thereof, according toclaim 5, wherein Ring C is a phenyl group substituted by 1-3substituents selected from the group consisting of a halogen atom, acyano group, a lower alkyl group, a halo-lower alkyl group, a loweralkoxy group, a halo-lower alkoxy group, and a mono- or di-loweralkylamino group; or a heterocyclyl group substituted by a substituentselected from the group consisting of a halogen atom, a cyano group, alower alkyl group, a halo-lower alkyl group, a lower alkoxy group, and ahalo-lower alkoxy group.
 7. The compound, or a pharmaceuticallyacceptable salt thereof, according to claim 6, wherein Ring C is aphenyl group substituted by a halogen atom, a cyano group, a lower alkylgroup, a halo-lower alkyl group, a lower alkoxy group, or a halo-loweralkoxy group; or a heterocyclyl group substituted by a halogen atom, acyano group, a lower alkyl group, or a lower alkoxy group.
 8. Thecompound, or a pharmaceutically acceptable salt thereof, according toclaim 5, wherein Ring C is a phenyl group substituted by a halogen atomor a cyano group, or a pyridyl group substituted by a halogen atom. 9.The compound, according to claim 1, wherein the compound is selectedfrom the group consisting of:1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethylyl]benzene;1-(β-D-glucopyranosyl)-4-chloro-3-[5-(3-cyanophenyl)-2-thienylmethyl]benzene;1-(β-D-glucopyranosyl)-4-chloro-3-[(5-(4-cyanophenyl)-2-thienylmethyl]benzene;1-(β-D-glucopyranosyl)-4-methyl-3-[5-(6-fluoro-2-pyridyl)-2-thienylmethyl]benzene;1-(β-D-glucopyranosyl)-4-chloro-3-[5-(6-fluoro-2-pyridyl)-2-thienylmethyl]benzene;1-(β-D-glucopyranosyl)-4-methyl-3-[5-(3-difluoromethyl-phenyl)-2-thienylmethyl]benzene;1-(β-D-glucopyranosyl)-4-methyl-3-[5-(3-cyanophenyl)-2-thienylmethyl]benzene;1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-cyanophenyl)-2-thienylmethyl]benzene;and1-(β-D-glucopyranosyl)-4-chloro-3-[5-(6-fluoro-3-pyridyl)-2-thienylmethyl]benzene;or a pharmaceutically acceptable salt thereof. 10.1-(β-D-glucopyranosyl)-4-methyl-3-[5-(3-cyano-phenyl)-2-thienylmethyl]benzene,or a pharmaceutically acceptable salt thereof. 11.1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-cyano-phenyl)-2-thienylmethyl]benzene,or a pharmaceutically acceptable salt thereof. 12.1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluoro-phenyl)-2-thienylmethyl]benzene,or a pharmaceutically acceptable salt thereof. 13.1-(β-D-glucopyranosyl)-4-chloro-3-[5-(3-cyano-phenyl)-2-thienylmethyl]benzene,or a pharmaceutically acceptable salt thereof. 14.1-(β-D-glucopyranosyl)-4-methyl-3-[5-(6-fluoro-2-pyridyl)-2-thienylmethyl]benzene,or a pharmaceutically acceptable salt thereof. 15.1-(β-D-glucopyranosyl)-4-chloro-3-[5-(6-fluoro-2-pyridyl)-2-thienylmethyl]benzene,or a pharmaceutically acceptable salt thereof. 16.1-(β-D-glucopyranosyl)-4-chloro-3-[5-(6-fluoro-3-pyridyl)-2-thienylmethyl]benzene,or a pharmaceutically acceptable salt thereof.
 17. A pharmaceuticalcomposition, which comprises the compound as set forth in claim 1, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier or diluent.
 18. A process for preparing a compound offormula I:

wherein Ring A, Ring B, X and Y are as defined in claim 1, whichcomprises deprotecting a compound of formula II:

wherein Ring A, Ring B and Y are defined in claim 1 R^(11a) is ahydrogen atom or a protecting group for a hydroxy group and R^(11b),R^(11c) and R^(11d) are each independently a protecting group for ahydroxy group.
 19. A process for preparing a compound of formula I-a:

wherein Ring A, Ring B and Y are as defined in claim 1, which comprisesreducing a compound of formula III:

wherein Ring A, Ring B and Y are as defined in claim 1, and R¹² is alower alkyl group.
 20. A compound having the following structure:


21. A pharmaceutical composition which comprises the compound of claim20 and a pharmaceutically acceptable carrier or diluent. 22.1-(β-D-glucopyranosyl)-4-chloro-3-[5-(4-cyanophenyl)-2-thienylmethyl]benzeneor a pharmaceutically acceptable salt thereof. 23.1-(β-D-glucopyranosyl)-4-methyl-3-[5-(3-difluoromethyl-phenyl)-2-thienylmethyl]benzeneor a pharmaceutically acceptable salt thereof.
 24. The compound, or apharmaceutically acceptable salt thereof according to claim 1, whereinRing A is

wherein R^(1a) is a halogen atom, a hydroxy group, an alkoxy group, analkyl group, a haloalkyl group, a haloalkoxy group, a hydroxyalkylgroup, an alkoxyalkyl group, an alkoxyalkoxy group, an alkenyl group, analkynyl group, a cycloalkyl group, a cycloalkylidenemethyl group, acycloalkenyl group, a cycloalkyloxy group, a phenyl group, aphenylalkoxy group, a cyano group, a nitro group, an amino group, amono- or di-alkylamino group, an alkanoylamino group, a carboxyl group,an alkoxycarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoylgroup, an alkanoyl group, an alkylsulfonylamino group, aphenylsulfonylamino group, an alkylsulfinyl group, an alkylsulfonylgroup, or a phenylsulfonyl group, and R^(2a) and R^(3a) are hydrogen.25. The compound, or a pharmaceutically acceptable salt thereofaccording to claim 24, wherein R^(1a) is a halogen atom or an alkylgroup, and R^(2a) and R^(3a) are hydrogen.
 26. The compound, or apharmaceutically acceptable salt thereof according to claim 1, whereinRing A is

wherein R^(1b), R^(2b), and R^(3b) are as defined in claim 1.